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the use of various imaging techniques in post - treatment assessment of head neck cancer is gradually on the rise , though clinical examinations at periodic intervals still remains the mainstay of follow - up .
18f fdg pet / ct is increasingly used in the post - treatment setting to diagnose residual / recurrent disease early so that appropriate treatment can be initiated .
the effects of multimodality treatment such as surgery , radiation , and chemotherapy can distort normal anatomical landmarks induce inflammation and infection , which can mask disease .
it is important to understand the anatomical and functional effects as well as complications produced by these treatment modalities in order to diagnose the resultant imaging pitfalls on fdg pet / ct .
knowledge of the common and unusual patterns of loco - regional recurrent disease and distant metastases on fdg pet / ct is also crucial in the post - treatment assessment of head - neck cancer patients .
radiation therapy alone or in combination with chemotherapy is often used to treat head - neck cancer patients .
there are several tissue changes , which are a result of early reaction to radiation .
these include thickening of the skin and platysma , stranding of the subcutaneous fat , pharyngeal and laryngeal wall thickening and increased vascularity of the major and minor salivary glands .
edema , inflammation , and increased vascularity in these structures lead to a pattern of fdg uptake which is low grade , diffuse , symmetrical , and restricted to the radiation field [ figure 1 ] .
these findings are seen during the course or within 3 months of radiation therapy and are often reversible .
several muscle groups within the radiation field also demonstrate an elevated fdg activity which can be potentially confused with neoplastic uptake .
however , absence of a mass lesion on ct and reduction over time differentiate an inflammatory or physiological uptake from disease .
axial pet and fused pet / ct images show diffuse symmetrical fdg uptake in the tongue and oropharynx ( arrows in the b and c ) and in the floor of mouth ( arrows in e and f ) .
diffuse low intensity fdg uptake is also seen in the neck muscles ( arrowheads in b , c , e , f ) .
diffuse uptake is seen within a few days of radiation and can last up to 810 weeks timing of pet / ct after radiation therapy is an important and often debated clinical issue .
performing pet / ct as early as possible to detect recurrent disease seems logical as salvage treatment can be initiated early enough to derive the best possible clinical benefit .
however , studies performed too early may lead to false positive as well as false negative results .
possible mechanism for false negative studies has been attributed to radiation induced vascular damage , which temporarily prevents concentration of radiotracer in the viable tumor cells .
imaging after a further few weeks delay in such cases may allow accumulation of tracer in the viable cells leading to a true positive pet result .
waiting too long to image might result in a loss of therapeutic window and also a more complicated surgical procedure due to fibrosis setting in . in order to strike a balance between misleading pet results when study is performed early and the clinical drawbacks of imaging late , a time interval of 12 weeks after completion of radiation therapy is generally recommended .
absence of fdg uptake at both the primary and nodal sites has a high negative predictive value in ruling out residual disease [ figure 2 ] .
studies have shown that a negative pet scan can potentially defer planned neck dissections after chemo - radiation therapy .
pretreatment coronal fused pet / ct ct studies show fdg avid right sided hypopharyngeal mass ( arrow in a and b ) .
study performed 8 weeks after completion of chemo - radiation therapy show complete metabolic and morphologic response ( arrow in c and d ) which rules out the possibility of residual disease
curative resection involves complex surgical procedures , which result in loss of symmetry and anatomical landmarks .
various reconstructive techniques are used to close the surgical defects and restore function which produces characteristic well - recognizable imaging findings .
procedures such as glossectomy , marginal or segmental mandibulectomy , maxillectomy leave large surgical defects , which are closed by flaps and grafts . pectoralis
myocutaneous flap is an example of a composite flap which is often used for reconstruction of large surgical defects in the face , tongue , and skull base .
they can be recognized by the well marginated soft tissue / muscle density at the site of the defect and is often accompanied by fat density [ figure 3a , b ] produced by a denervation atrophy and fatty replacement of the muscle .
normal symmetric pattern of tracer concentration is disturbed due to absence of physiological fdg uptake at the resected and reconstructed site [ figure 3b and d ] . in patients undergoing total laryngo - pharyngectomy ,
a neopharynx is reconstructed which can be recognized as a simple tubular structure sans the accompanying complex anatomy of hypopharynx and larynx [ figure 4 ] .
the neopharynx is often constructed by using a jejunal free flap , which is recognised recognized by the mesenteric fat along with its native vessels .
axial fused pet / ct images show myocutaneous flap with fat density used to reconstruct the defect after hemimandibulectomy ( arrow in a ) and mandibular symphysectomy ( arrow in b ) performed for buccal cancer absence of normal physiological fdg uptake in the reconstructed flap ( arrowheads in a and b ) tissue changes after surgery .
axial ct shows a reconstructed neopharynx after a laryngopharyngectomy seen as a tubular structure ( arrow in a ) .
diffuse low grade physiological uptake is seen around the neopharynx ( arrow head in b )
during or after the course of treatment pitfalls in image interpretation can occur due to several factors .
asymmetric nature of physiological uptake , inflammations / infective processes , and treatment - related complications are some of the common causes of false positive results leading to imaging pitfalls .
sometimes , as a consequence of late effects of radiation therapy , there is a reduction of the normal physiological fdg uptake in structures such as the salivary glands and pharyngeal mucosal lining on the side of the therapy , leading to an appearance of asymmetric increased uptake in the normal tissues on the contralateral side [ figure 5 ] .
coronal and axial ( pet ) and fused pet / ct images show reduction in physiological uptake ( arrows in a , b , d ) on the left side due to long term effects of radiation therapy .
note the relative increase in physiological uptake in the parotid and submandibular glands and the oropharynx on the contralateral normal side which can mimic pathology ( arrowheads in a and d ) absence of physiological fdg uptake in the region of the surgically removed part and persistence of physiological uptake in the normal contralateral side produces an appearance of asymmetric tracer concentration that can mimic disease [ figure 6 ] .
occasionally , after partial resection of an organ such as the tongue , the remnant portion retains its physiological uptake , which appears focal in nature mimicking disease [ figure 7 ] .
after extensive jaw surgeries and reconstructive procedures , the altered mechanics of mastication can result in physiologically increased focal uptake in the adjacent masticator muscles that can be mistaken for disease [ figure 8 ] .
axial ct shows changes of right hemiglossectomy with a myocutaneous flap containing fat ( arrowhead in a ) .
axial pet and fusion pet / ct show physiological uptake in the remnant tongue which is focal and asymmetric in nature ( arrows in b and c ) and can potentially mimic disease pitfalls of due asymmetric physiological uptake .
coronal pet and fusion pet / ct show physiological uptake along the right side of the oral cavity and the floor of mouth which is asymmetric in nature ( arrows in b and c ) and can potentially mimic disease .
note the absence of normal physiological uptake on the left side ( arrowheads in b and c ) .
this pattern was seen more than a year after treatment pitfalls of due asymmetric physiological uptake .
axial pet and fusion pet / ct show focal asymmetric uptake in the left masseter which is physiological in nature ( arrows in a and b ) and is produced due to altered mechanics of mastication secondary to jaw surgery physiological uptake in the tongue tip and oral cavity arising due to close approximation of tongue and palate , buccal and gingival mucosae can be better resolved by performing certain maneuvers like puffing the cheek and placing a gauzegauze that can help mouth opening .
surgical complications occur early and include serous collections , infections , abscess and fistula formation , flap necrosis .
benign serous collections are self - limiting and should be distinguished from infected abscesses that might need a drainage procedure .
benign serous collections also called seromas usually do not show any fdg avidity unless they get infected . on fdg pet / ct abscesses
show a rim of tracer uptake in the periphery with a photopenic center which corresponds to a hypodense collection on ct with air pockets seen occasionally .
linear fdg uptake is seen along the fistulous communications associated with abscesses [ figure 9 ] .
these complications occur at the site of surgical resection and reconstructed flaps in the head neck region .
rarely , one can come across infections / inflammations at the site of the donor flap in the chest or the abdominal wall and focal tracer uptake in this region can potentially mimic metastatic disease [ figure 10 ] .
axial fused pet / ct shows an intense focus of fdg uptake in the infratemporal fossa mimicking disease recurrence ( arrow in b ) .
corresponding contrast ct image shows a hypodense collection with an air pocket ( arrow in a ) suggestive of an abscess .
note the linear fdg uptake along the enhancing fistulous tract opening on the skin surface .
( arrowheads in a and b ) pitfalls due to treatment related complications ( surgery ) .
coronal mip image shows an intense focus of fdg uptake in the left hemithorax ( arrow in a ) which appears to be metastatic disease .
fused pet / ct shows focal uptake in the anterior chest wall ( arrow in c ) which was the site for the pmmc flap .
arrowhead in b ) radiation toxicity can lead to intense inflammatory changes in the mucosal structures and the soft tissues of the neck that can cause intense fdg accumulation [ figure 11 ] .
coronal pet ( b ) and fused pet / ct ( c ) shows intense fdg uptake in the naso , oro , and hypopharyngeal structures and the soft tissue of the neck bilaterally , with associated ill - defined fat stranding ( a arrowhead ) .
such intense non - infective inflammation is seen on rare occasions after radiation and should not be confused with recurrence radiation induced necrosis can occur in bones ( osteoradionecrosis [ orn ] ) , cartilage ( chondronecrosis / laryngeal necrosis ) and even in irradiated soft tissues .
osteoradionecrosis ( orn ) occurs due to devitalization of irradiated bone which gets exposed through the skin and mucosa and remains without healing for at least 3 months .
the risk of orn is greatest at 6 - 12 months after radiation therapy and it is uncommon to see orn at radiation doses below 60 gy .
lytic destruction , cortical erosion and fragmentation of the mandible with associated fistulae and soft tissue thickening are some of the features seen on ct scan [ figure 12 ] . increased fdg avidity is seen in areas affected by orn [ figure 12 ] , but its specificity in differentiating viable tumor from radionecrosis is not reported to be very high .
orn can occur at rare sites such as the hyoid bone and increased fdg avidity may lead to the erroneous diagnosis of viable disease unless the physician is aware of its occurrence [ figure 13 ] .
characteristics osseous changes of orn and absence of associated soft tissue lesion make the diagnosis of radiation necrosis more likely
axial ct in soft tissue ( a ) and bone window settings ( b ) show soft tissue thickening , erosion and fragmentation of the mandible ( arrows ) .
coronal fused pet / ct shows intense fdg uptake restricted to right hemimandible ( arrowhead in c and d ) .
findings suggest the diagnosis of orn pitfalls due to treatment related complications - osteoradionecrosis [ orn ] .
axial fused pet / ct shows intense fdg uptake along the hyoid bone ( arrowhead in a and b ) .
axial ct shows subtle erosion of the hyoid bone along with a small collection and air pockets ( arrows in c and d ) .
sometimes , as a consequence of late effects of radiation therapy , there is a reduction of the normal physiological fdg uptake in structures such as the salivary glands and pharyngeal mucosal lining on the side of the therapy , leading to an appearance of asymmetric increased uptake in the normal tissues on the contralateral side [ figure 5 ] .
coronal and axial ( pet ) and fused pet / ct images show reduction in physiological uptake ( arrows in a , b , d ) on the left side due to long term effects of radiation therapy .
note the relative increase in physiological uptake in the parotid and submandibular glands and the oropharynx on the contralateral normal side which can mimic pathology ( arrowheads in a and d ) absence of physiological fdg uptake in the region of the surgically removed part and persistence of physiological uptake in the normal contralateral side produces an appearance of asymmetric tracer concentration that can mimic disease [ figure 6 ] .
occasionally , after partial resection of an organ such as the tongue , the remnant portion retains its physiological uptake , which appears focal in nature mimicking disease [ figure 7 ] .
after extensive jaw surgeries and reconstructive procedures , the altered mechanics of mastication can result in physiologically increased focal uptake in the adjacent masticator muscles that can be mistaken for disease [ figure 8 ] .
axial ct shows changes of right hemiglossectomy with a myocutaneous flap containing fat ( arrowhead in a ) .
axial pet and fusion pet / ct show physiological uptake in the remnant tongue which is focal and asymmetric in nature ( arrows in b and c ) and can potentially mimic disease pitfalls of due asymmetric physiological uptake .
coronal pet and fusion pet / ct show physiological uptake along the right side of the oral cavity and the floor of mouth which is asymmetric in nature ( arrows in b and c ) and can potentially mimic disease .
note the absence of normal physiological uptake on the left side ( arrowheads in b and c ) .
this pattern was seen more than a year after treatment pitfalls of due asymmetric physiological uptake .
axial pet and fusion pet / ct show focal asymmetric uptake in the left masseter which is physiological in nature ( arrows in a and b ) and is produced due to altered mechanics of mastication secondary to jaw surgery physiological uptake in the tongue tip and oral cavity arising due to close approximation of tongue and palate , buccal and gingival mucosae can be better resolved by performing certain maneuvers like puffing the cheek and placing a gauzegauze that can help mouth opening .
surgical complications occur early and include serous collections , infections , abscess and fistula formation , flap necrosis .
benign serous collections are self - limiting and should be distinguished from infected abscesses that might need a drainage procedure .
benign serous collections also called seromas usually do not show any fdg avidity unless they get infected . on fdg pet / ct abscesses
show a rim of tracer uptake in the periphery with a photopenic center which corresponds to a hypodense collection on ct with air pockets seen occasionally .
linear fdg uptake is seen along the fistulous communications associated with abscesses [ figure 9 ] .
these complications occur at the site of surgical resection and reconstructed flaps in the head neck region .
rarely , one can come across infections / inflammations at the site of the donor flap in the chest or the abdominal wall and focal tracer uptake in this region can potentially mimic metastatic disease [ figure 10 ] .
axial fused pet / ct shows an intense focus of fdg uptake in the infratemporal fossa mimicking disease recurrence ( arrow in b ) .
corresponding contrast ct image shows a hypodense collection with an air pocket ( arrow in a ) suggestive of an abscess .
note the linear fdg uptake along the enhancing fistulous tract opening on the skin surface .
( arrowheads in a and b ) pitfalls due to treatment related complications ( surgery ) .
coronal mip image shows an intense focus of fdg uptake in the left hemithorax ( arrow in a ) which appears to be metastatic disease .
fused pet / ct shows focal uptake in the anterior chest wall ( arrow in c ) which was the site for the pmmc flap .
arrowhead in b ) radiation toxicity can lead to intense inflammatory changes in the mucosal structures and the soft tissues of the neck that can cause intense fdg accumulation [ figure 11 ] .
coronal pet ( b ) and fused pet / ct ( c ) shows intense fdg uptake in the naso , oro , and hypopharyngeal structures and the soft tissue of the neck bilaterally , with associated ill - defined fat stranding ( a arrowhead ) .
such intense non - infective inflammation is seen on rare occasions after radiation and should not be confused with recurrence radiation induced necrosis can occur in bones ( osteoradionecrosis [ orn ] ) , cartilage ( chondronecrosis / laryngeal necrosis ) and even in irradiated soft tissues .
osteoradionecrosis ( orn ) occurs due to devitalization of irradiated bone which gets exposed through the skin and mucosa and remains without healing for at least 3 months .
the risk of orn is greatest at 6 - 12 months after radiation therapy and it is uncommon to see orn at radiation doses below 60 gy .
lytic destruction , cortical erosion and fragmentation of the mandible with associated fistulae and soft tissue thickening are some of the features seen on ct scan [ figure 12 ] .
increased fdg avidity is seen in areas affected by orn [ figure 12 ] , but its specificity in differentiating viable tumor from radionecrosis is not reported to be very high .
orn can occur at rare sites such as the hyoid bone and increased fdg avidity may lead to the erroneous diagnosis of viable disease unless the physician is aware of its occurrence [ figure 13 ] .
characteristics osseous changes of orn and absence of associated soft tissue lesion make the diagnosis of radiation necrosis more likely
( b ) show soft tissue thickening , erosion and fragmentation of the mandible ( arrows ) .
coronal fused pet / ct shows intense fdg uptake restricted to right hemimandible ( arrowhead in c and d ) .
findings suggest the diagnosis of orn pitfalls due to treatment related complications - osteoradionecrosis [ orn ] .
axial fused pet / ct shows intense fdg uptake along the hyoid bone ( arrowhead in a and b ) .
axial ct shows subtle erosion of the hyoid bone along with a small collection and air pockets ( arrows in c and d ) .
fdg pet / ct has been used to detect recurrent disease in the head and neck cancer patients .
it can confirm the site of clinically suspected local recurrence and determine its true extent .
recurrences at the site of the treated primary disease , subtle disease in the reconstructed flaps and nodal / soft tissue recurrence in the irradiated neck , the clinical assessment of which is difficult can be seen on pet / ct as enhancing lesions with intense fdg avidity [ figures 14 and 15 ] . at the same time
, it can pick up distant failures with a good accuracy and thus is performed before salvage surgery can potentially change the intended treatment plan .
in addition to common sites of distant metastases like the lungs and bones , pet / ct has the potential to unmask second primaries as well as certain unusual and rare metastatic sites such as the subcutaneous tissue , muscles , and feeding stomies [ figures 16 and 17 ] . recurrent disease . operated case of buccal cancer .
coronal mip shows intense foci of fdg uptake on the left side of the face and neck ( arrowhead and arrows in a ) .
axial fused pet / ct shows fdg avid recurrent nodule in the pmmc flap ( arrowhead in b and c ) and a metastatic cervical lymph node ( arrow in d and e ) recurrent disease .
sagittal mip shows foci of fdg uptake in the face ( arrows in a ) .
axial fused pet / ct ( arrowhead in b and c ) shows subtle uptake at the cut margin of the mandible due to local recurrence as well as metastatic deposit in the pterygopalatine fossa ( arrows in d and e ) distant metastases .
fusion pet / ct images show metastatic deposits in spleen ( b ) , lungs ( c ) , liver ( d ) , bone ( e ) , subcutaneous region ( f ) and muscle ( g ) distant metastases ( unusual sites ) . operated case of base tongue cancer with feeding gastrostomy .
sagittal pet and pet / ct images show a fdg avid mass in the anterior abdominal wall at the site of the gastrostomy ( arrows in a - b ) s / o metastatic deposit . local recurrence in the tongue base
fdg pet / ct is a useful modality in the post - treatment setting of head and neck cancers .
knowledge of certain characteristic imaging appearances and a few commonly encountered treatment related complications is important to avoid pitfalls in post - treatment imaging .
understanding the role of fdg pet / ct in detecting local recurrence and distant metastases plays a crucial role in deciding salvage treatment . | majority of patients with head and neck cancer are treated with combined treatment regimes such as surgery , radiation therapy , and chemotherapy .
the loss of structural symmetry and imaging landmarks as a result of therapy makes post - treatment imaging a daunting task on conventional modalities like computed tomography ( ct ) scan and magnetic resonance imaging ( mri ) as well as on 18 fluorine - fluorodeoxyglucose positron emission tomography / computed tomography ( 18f fdg pet / ct ) .
combined multimodality treatment approach causes various tissue changes that give rise to a spectrum of findings on fdg pet / ct imaging , which are depicted in this atlas along with a few commonly encountered imaging pitfalls .
the incremental value of fdg pet / ct in detecting locoregional recurrences in the neck as well as distant failures has also been demonstrated . | [
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the bacterial isolates were collected throughout finland during 19982007 as described ( 10 ) . of
bionumerics version 5.1 software ( applied maths , kortrijk , belgium ) was used for sequence assembly .
allele numbers , sequence types ( sts ) , and clonal complexes ( ccs ) were assigned by using the pubmlst database ( 5 ) .
a serum sensitivity assay was conducted with 73 c. jejuni isolates according to a described protocol ( 8) . the same pool of serum samples from 10 healthy blood donors was used in all experiments . c. jejuni
all statistical analyses were performed by using graphpad prism version 4.03 ( graphpad software , san diego , ca , usa ) and pasw statistics version 18 ( spss inc . , chicago , il , usa ) .
a total of 72 c. jejuni isolates from blood were successfully typed by mlst ; 1 isolate had a mixed mlst pattern .
five isolates were in unassigned sts , and the rest were distributed among 11 ccs ( table ) .
genetic relatedness of these isolates was further confirmed by using pulsed - field gel electrophoresis .
* mlst , multilocus sequence typing ; st , sequence type ; nd , none detected .
however , bacteremia episodes caused by st-677 cc isolates were exclusively diagnosed during the seasonal peak during may august ( figure 1 ) . of c. jejuni blood culture isolates detected during may august , most ( 64% ) were st-677 cc .
furthermore , st-677 cc was the most prevalent complex in 4 geographic regions of finland . annual and seasonal distribution of 72 camplyobacter jejuni blood culture isolates belonging either to the st-677 clonal complex ( cc ) or to the other multilocus sequence typing ( mlst ) ccs .
one isolate with a mixed multilocus sequence type was not included . c. jejuni bacteremia was diagnosed during may august ( m a ) or during any other month of the year ( o ) .
susceptibility to human serum varied between c. jejuni isolates from different ccs ( figure 2 ) .
st-677 cc isolates were significantly less susceptible to human serum than all other isolates ( p<0.0001 ) .
st-45 cc isolates were significantly more susceptible to human serum than all other isolates ( p<0.0001 ) .
percentage of surviving bacteria in human serum for 73 blood culture isolates of campylobacter jejuni ( cj ) , grouped according to major multilocus sequence typing clonal complexes ( ccs ) , and for controls c. jejuni cj11168 and c. fetus .
we characterized a unique collection of 73 c. jejuni isolates from blood obtained during a nationwide study in finland over a 10-year period . despite the high population diversity of c. jejuni , nearly half of the isolates from blood showed clustering within the st-677 cc , a rare cc in other countries ( 12,13 ) .
thus , invasiveness of blood culture isolates could not be solely explained by their serum resistance , although the predominant isolates of st-677 cc were more serum resistant than other isolates . c. jejuni has high st diversity . as of may 2 , 2013 , a total of 6,564 sts were registered ( 5 ) . in this study , we detected clustering of c. jejuni isolates from blood in an uncommon st-677 cc .
further studies are needed to clarify whether bacterial characteristics might explain this finding . in our previous study , which included human fecal c. jejuni isolates obtained in finland from the mid-1990s through 2007 ,
which is nearly the same period as in the current nationwide study , 11.7% of the isolates belonged to st-677 cc ( 11 ) .
the 2 most prevalent ccs in that study , st-45 cc ( 43.6% of fecal isolates ) and st-21 cc ( 19.4% of fecal isolates ) , were detected only among 12 ( 16% ) and 10 ( 14% ) of blood culture isolates , respectively , in the present study .
st-45 cc and st-21 cc have been shown to be prevalent in several countries ( 4,13 ) . however , our results suggest that these 2 ccs are not common among c. jejuni isolates from blood in finland , which cluster more in the st-677 cc . on the basis of the present results , we speculate that st-677 cc might have a special invasive capability or has adapted to the environment in finland .
in general , complement - mediated killing of serum - susceptible isolates plays a major role in restricting access of pathogens to the bloodstream . however , available information about possible serum sensitivity of c. jejuni isolates from blood is scarce ( 8,9 ) . in our study of nonselected c. jejuni isolates from blood , susceptibility to human serum varied according to mlst cc . in conclusion , in this nationwide study during a 10-year period in finland , we found by mlst analysis that half of the bacteremia isolates of c. jejuni clustered within an otherwise uncommon st-677 cc . whether this finding indicates special adaptation of st-677 cc to finland or to the human bloodstream
our findings emphasize the role of using well - defined clinical materials in studies on bacterial pathogenicity and severity of human disease . | campylobacter jejuni bacteria are highly diverse enteropathogens .
seventy - three c. jejuni isolates from blood collected in finland were analyzed by multilocus sequence typing and serum resistance .
approximately half of the isolates belonged to the otherwise uncommon sequence type 677 clonal complex .
isolates of this clonal complex were more resistant than other isolates to human serum . | [
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in particular , osteoimmunology investigates how the immune system impacts on bone turnover in physiological and pathological conditions through the immunoskeletal interface .
researchers recently hav - egained better understanding of the dialogue between immune and bone cells and a new reading register of bone remodeling is emerging , in which the various phases of bone formation and resorption , that coexist in a dynamic equilibrium , are under strict immunological control .
bone and immune system are functionally integrated through complex homeostatic networks and , in all respects , osteoporosis could be considered a chronic immune mediated inflammatory disease which shares clinical and biological features with many other inflammatory conditions , as well as of other immune mediated diseases . in this context immune and bone systems appear to be integrated and sharing signaling pathways and regulatory mechanisms whose understanding provides a framework for obtaining new insights for the discovery of novel treatments for diseases related to both systems .
thus osteoimmunology appears definitely as an interdisciplinary research and clinical field which also allowed new pathogenetic and clinical interpretations of well - known and common diseases , such as osteoporosis .
its fields of interest are constantly expanding , thus enriching with an increasing number of translational implications , even in clinical practice and in various branches of medicine . here , the most important concepts in osteoimmunology are addressed in the context of physiopatological states bridging these two organ systems , including osteoporosis , ageing , menopause , inflammatory arthritis , cancer , dysmetabolism and neurological disorders .
purpose of this review is to outline a new panorama of osteoimmunology that is not limited to immune mediated bone turnover but also consider , in the light of the latest findings in this field , interesting connections with other systems and regulatory functions over bone remodeling .
bone is a dynamic tissue formed by a protein and mineral salt matrix in which are embedded the bone cells , osteocytes ( ocy ) , osteoblasts ( ob ) and osteoclasts ( oc ) . in addition , many other types of cells take part in bone composition , including cartilage , stromal , hematopoietic and mesenchimal stem cells , all linked by a dense network of signals .
antagonistic signaling between skeletal stem cell - derived subsets is a key mechanism in skeletal subset lineage commitment .
bone tissue undergoes continuous adaptation during lifetime to preserve the structure of the skeleton and to control the mineral homeostasis .
bone turnover requires two coordinated processes : bone formation , driven by ob and bone resorption , mediated by oc .
ocy , through a complex network of tiny channels , transmit mechanical and microtraumatic signals leading to the activation of repair processes .
moreover , ocy synthesize the bone matrix proteins which , along with the mineral component , determine the quality of the bone .
ob are the precursors of ocy , i.e , the structural cells in the bone , and interact with oc to drive their differentiation and function .
the mesenchymal stem cell ( msc ) from which the ob originate , can also give rise to chondrocytes , marrow stromal cells , and adipocytes .
there are multiple subpopulations of perisinusoidal mesenchymal stem / progenitor cells ( mspcs ) , that have specific relationships with the different kinds of niche , i.e. the surrounding microenvironment in which the self - renewal and multilineage stem cells proliferate and differentiate [ 7 - 9 ] .
the stem cells that maintain and repair the postnatal skeleton is an osteochondroreticular ( ocr ) stem cell that generate ob , chondrocytes , and reticular marrow stromal cells , but not adipocytes .
they are characterized by the expression of the bone morphogenetic protein ( bmp ) antagonist gremlin 1 ( grem 1 ) .
the perisinusoidal msc population also contains nes - gfp , leptin receptor ( lepr)-cre and cd146 expressing cells with osteogenic and adipogenic potential .
the osteoblast precursor cells ( obp ) after increasing the osteopontin receptor ( cd44 ) and the receptor for stromal cell - derived factor 1 - sdf1 ( cxcr4 ) expression , migrate and become mature ob , attracted by vascular endothelial cells expressing sdf1 along chemotactic gradients into regions of bone formation .
oc are multinucleated myeloid cells , specialized to remove mineralized bone matrix through the production of lysosomal enzymes , such as tartrate - resistant acid phosphatase ( trap ) and catepsin k , against which a selective inhibitor ( odanacatib ) has been recently synthesized to be employed in osteoporotic patients .
they derive from a bone marrow precursor which gives rise also to professional antigen presenting cells ( apc ) , i.e. dendritic cells and macrophages .
ob , ocy and oc continuously communicate with each other to optimize the quality of the bone .
for example , ob provide essential signals for the differentiation of the myeloid lineage precursors of oc by producing macrophage colony - stimulating factor ( m - csf ) , receptor activator of nuclear factor - kb ( nf - kb ) ligand ( rankl ) and other co - stimulatory factors .
the binding of rank receptor on oc and their precursors by its ligand rankl , expressed by ob and stromal cells , is the main activation signal for bone resorption .
the ob derived m - csf links to its receptor c - fms on the surface of osteoclast cell precursors ( ocp ) , enabling the rank / rankl signal .
osteoprotegerin ( opg ) inhibits osteoclastogenesis by acting as a decoy receptor of rankl , thus preventing bone resorption .
rank receptor on oc , through the adapter protein tumor - necrosis - factor - receptor - associated factor 6 ( tr - af6 ) , bound to its cytoplasmic tail , activates nf - kb and other transcription factors , such as mapks , c - fos , activator protein 1 ( ap1 ) , up to nuclear factor of activated t cells ( nfatc1 ) , the hub of various signaling pathways .
simultaneously , the activation of rank induces the phosphorylation of ig - like receptor associated adaptor proteins , such as the immunoreceptor tyrosine - based activation motif ( itam ) and fc - receptor common gamma ( fcr ) subunit . in the nucleus nfatc1 , together with other transcription factors , such as ap1 , pu.1 , microphthalmia - associated transcription factor ( mitf ) and cyclic amp responsive - element - binding protein ( creb ) , induces oc specific genes , including those codifying for calcitonin receptor , cathepsin k and trap , leading to oc differentiation and proliferation .
many other receptor pathways interact with rank , some costimulators and amplificators , others inhibitors and modulators , and many of these are shared by immune cells . an inhibitor receptor system for rank signal is ephrin ( eph ) b2/b4 .
ephb2 receptor on oc , stimulated by ephb4 ligand on ob , inhibits the oc differentiation blocking c - fos and the nfatc1 transcriptional cascade .
a peculiar property of this membrane receptor complex is its capacity to control bone turnover through bidirectional signals : the cell expressing the receptor and the one that expresses the ligand influence each other at the same time .
therefore , ephb4 activation on ob , through the induction of osteogenetic regulatory genes , contemporaneously favours the coupling of bone formation and resorption .
the canonical wingless ( wnt)/ catenin pathway , involved mainly in the response to mechanical load , promotes differentiation , proliferation and mineralization activity of ob and also inhibits their apoptosis .
it encompasses a family of proteins that bind to complex transmembrane receptors , formed by the association of frizzled ( fz ) proteins and low density lipoprotein related receptors ( lrp-5 , lrp-6 ) which stabilize the -catenin substrate that concentrates in the cytosol and migrates into the obp nucleus to regulate the transcription of target genes to induce ob differentiation and bone formation .
wnt signaling inhibits msc commitment towards adipogenic and chondrogenic lineages , stimulating the differentiation towards osteoblastogenesis .
wnt--catenin signaling also indirectly inhibits osteoclastogenesis and bone resorption by increasing opg secretion in ob and ocy .
the bmp pathway acts as a wnt associative stimulator signal in skeletogenesis by expanding primitive mesenchymal cells and thus laying the foundation for subsequent endochondral ossification . at the same time , various natural inhibitors , produced both by ob and ocy , exert a negative feed - back control on wnt system , such as the wnt/-catenin signaling pathway inhibitor dickkopf homolog-1 ( dkk-1 ) , the secreted frizzled related protein ( sfrp ) and the sclerostin , synthesized by the sost gene , which binds to lrp5/6 receptors .
the inflammatory cytokine tumor necrosis factor- ( tnf- ) induces ob apoptosis and reduces osteoblastogenesis by stimulating dkk-1 and sost expression .
cortison augments dkk-1 and sfrp expression thus suppressing the wnt/-catenin signal on ob inducing osteoporosis .
an anti - sclerostin moab has recently been produced as a new osteoanabolic drug useful in the therapy of osteoporosis .
other potential osteoanabolic drugs acting on the wnt pathway are also dkk inhibitor molecules , now in the experimental stage .
bone is a dynamic tissue formed by a protein and mineral salt matrix in which are embedded the bone cells , osteocytes ( ocy ) , osteoblasts ( ob ) and osteoclasts ( oc ) . in addition , many other types of cells take part in bone composition , including cartilage , stromal , hematopoietic and mesenchimal stem cells , all linked by a dense network of signals .
antagonistic signaling between skeletal stem cell - derived subsets is a key mechanism in skeletal subset lineage commitment .
bone tissue undergoes continuous adaptation during lifetime to preserve the structure of the skeleton and to control the mineral homeostasis .
bone turnover requires two coordinated processes : bone formation , driven by ob and bone resorption , mediated by oc .
ocy , through a complex network of tiny channels , transmit mechanical and microtraumatic signals leading to the activation of repair processes .
moreover , ocy synthesize the bone matrix proteins which , along with the mineral component , determine the quality of the bone .
ob are the precursors of ocy , i.e , the structural cells in the bone , and interact with oc to drive their differentiation and function .
the mesenchymal stem cell ( msc ) from which the ob originate , can also give rise to chondrocytes , marrow stromal cells , and adipocytes .
there are multiple subpopulations of perisinusoidal mesenchymal stem / progenitor cells ( mspcs ) , that have specific relationships with the different kinds of niche , i.e. the surrounding microenvironment in which the self - renewal and multilineage stem cells proliferate and differentiate [ 7 - 9 ] .
the stem cells that maintain and repair the postnatal skeleton is an osteochondroreticular ( ocr ) stem cell that generate ob , chondrocytes , and reticular marrow stromal cells , but not adipocytes .
they are characterized by the expression of the bone morphogenetic protein ( bmp ) antagonist gremlin 1 ( grem 1 ) .
the perisinusoidal msc population also contains nes - gfp , leptin receptor ( lepr)-cre and cd146 expressing cells with osteogenic and adipogenic potential .
the osteoblast precursor cells ( obp ) after increasing the osteopontin receptor ( cd44 ) and the receptor for stromal cell - derived factor 1 - sdf1 ( cxcr4 ) expression , migrate and become mature ob , attracted by vascular endothelial cells expressing sdf1 along chemotactic gradients into regions of bone formation .
oc are multinucleated myeloid cells , specialized to remove mineralized bone matrix through the production of lysosomal enzymes , such as tartrate - resistant acid phosphatase ( trap ) and catepsin k , against which a selective inhibitor ( odanacatib ) has been recently synthesized to be employed in osteoporotic patients .
they derive from a bone marrow precursor which gives rise also to professional antigen presenting cells ( apc ) , i.e. dendritic cells and macrophages .
ob , ocy and oc continuously communicate with each other to optimize the quality of the bone .
for example , ob provide essential signals for the differentiation of the myeloid lineage precursors of oc by producing macrophage colony - stimulating factor ( m - csf ) , receptor activator of nuclear factor - kb ( nf - kb ) ligand ( rankl ) and other co - stimulatory factors .
the binding of rank receptor on oc and their precursors by its ligand rankl , expressed by ob and stromal cells , is the main activation signal for bone resorption .
the ob derived m - csf links to its receptor c - fms on the surface of osteoclast cell precursors ( ocp ) , enabling the rank / rankl signal .
osteoprotegerin ( opg ) inhibits osteoclastogenesis by acting as a decoy receptor of rankl , thus preventing bone resorption .
rank receptor on oc , through the adapter protein tumor - necrosis - factor - receptor - associated factor 6 ( tr - af6 ) , bound to its cytoplasmic tail , activates nf - kb and other transcription factors , such as mapks , c - fos , activator protein 1 ( ap1 ) , up to nuclear factor of activated t cells ( nfatc1 ) , the hub of various signaling pathways .
simultaneously , the activation of rank induces the phosphorylation of ig - like receptor associated adaptor proteins , such as the immunoreceptor tyrosine - based activation motif ( itam ) and fc - receptor common gamma ( fcr ) subunit . in the nucleus nfatc1 , together with other transcription factors , such as ap1 , pu.1 , microphthalmia - associated transcription factor ( mitf ) and cyclic amp responsive - element - binding protein ( creb ) , induces oc specific genes , including those codifying for calcitonin receptor , cathepsin k and trap , leading to oc differentiation and proliferation .
many other receptor pathways interact with rank , some costimulators and amplificators , others inhibitors and modulators , and many of these are shared by immune cells . an inhibitor receptor system for rank signal is ephrin ( eph ) b2/b4 .
ephb2 receptor on oc , stimulated by ephb4 ligand on ob , inhibits the oc differentiation blocking c - fos and the nfatc1 transcriptional cascade .
a peculiar property of this membrane receptor complex is its capacity to control bone turnover through bidirectional signals : the cell expressing the receptor and the one that expresses the ligand influence each other at the same time .
therefore , ephb4 activation on ob , through the induction of osteogenetic regulatory genes , contemporaneously favours the coupling of bone formation and resorption . the canonical wingless ( wnt)/ catenin pathway , involved mainly in the response to mechanical load , promotes differentiation , proliferation and mineralization activity of ob and also inhibits their apoptosis .
it encompasses a family of proteins that bind to complex transmembrane receptors , formed by the association of frizzled ( fz ) proteins and low density lipoprotein related receptors ( lrp-5 , lrp-6 ) which stabilize the -catenin substrate that concentrates in the cytosol and migrates into the obp nucleus to regulate the transcription of target genes to induce ob differentiation and bone formation .
wnt signaling inhibits msc commitment towards adipogenic and chondrogenic lineages , stimulating the differentiation towards osteoblastogenesis .
wnt--catenin signaling also indirectly inhibits osteoclastogenesis and bone resorption by increasing opg secretion in ob and ocy .
the bmp pathway acts as a wnt associative stimulator signal in skeletogenesis by expanding primitive mesenchymal cells and thus laying the foundation for subsequent endochondral ossification . at the same time , various natural inhibitors , produced both by ob and ocy , exert a negative feed - back control on wnt system , such as the wnt/-catenin signaling pathway inhibitor dickkopf homolog-1 ( dkk-1 ) , the secreted frizzled related protein ( sfrp ) and the sclerostin , synthesized by the sost gene , which binds to lrp5/6 receptors .
the inflammatory cytokine tumor necrosis factor- ( tnf- ) induces ob apoptosis and reduces osteoblastogenesis by stimulating dkk-1 and sost expression .
cortison augments dkk-1 and sfrp expression thus suppressing the wnt/-catenin signal on ob inducing osteoporosis .
an anti - sclerostin moab has recently been produced as a new osteoanabolic drug useful in the therapy of osteoporosis .
other potential osteoanabolic drugs acting on the wnt pathway are also dkk inhibitor molecules , now in the experimental stage .
both clinical observations and basic research demonstrated that mediators driving inflammatory processes are also closely involved in bone remodeling .
inflammation and bone turnover share the same mediators , such as cytokines and transcription factors .
various molecules mediating communication between bone cells have been identified and several immunological mediators are involved in this crosstalk .
t lymphocytes resident in the bone marrow are the key immune cells that regulate bone remodeling and responsiveness of bone cells to parathyroid hormone ( pth ) , in physiological and pathological conditions . during inflammatory diseases or in conditions characterized by low - grade systemic inflammation , such as menopause and aging , oc bone resorption is driven by inflammatory cytokines produced by activated t lymphocytes .
however , bone marrow t cells also support bone homeostasis by inducing bone formation via direct interactions with bone cells .
two mechanisms are involved : the binding of t cell costimulatory molecules to their counter receptors on bone cells and their precursors , and the release of cytokines and wnt ligands that activate wnt signaling in osteoblastic cell lineage .
the final effect of t lymphocytes on bone depends on their activation state and their specific phenotype .
the prevailing bone marrow t cells are activated central memory cd8 + lymphocytes , secreting relatively high levels of effector cytokines , mainy tnf-. these cells are abundant in postmenopausal women with osteoporotic fractures .
t helper ( th17 ) cells are capable of stimulating bone resorption and play a pivotal role in the bone loss of inflammatory conditions such as psoriasis , rheumatoid arthritis , periodontal disease , and inflammatory bowel disease .
th17 cells induce osteoclastogenesis by secreting interleukin ( il)-17 , rankl , tnf- , il-1 , and il-6 , along with low levels of ifn-. moreover , il-17 stimulates the release of rankl by ob and ocy and upregulate rank expression on oc .
treg exert anti - osteo - clastogenic activity by producing suppressor cytokines , including il-4 , il-10 , and tgf- .
for example it is interesting to note how even the cells of the immune sytem , mainly activated t and b lymphocytes and dendritic cells , express rankl .
moreover , ran - kl , the principal osteoclastogenic mediator , stimulates bone resorption through the nfatc1 , which is also a crucial factor in the immune system regulation .
rankl , initially regarded as activator of apc by t lymphocytes , also plays an important role in the generation of treg , which suppress the development of cd8 + lymphocytes into cytotoxic cells .
the expression of rankl on t lymphocytes is also central for the differentiation of medullary epithelial cells which are responsible for self - reactive t lymphocyte negative selection in the thymus .
thus , depending on the context in which it acts , rankl can stimulate or suppress immune reactions .
other examples of shared receptor signals are the immunoglobulin ( ig)-like receptors which amplify the nfatc1 signal .
the toll like receptors ( tlr ) , stimulated by pathogen associated molecular patterns ( pamp ) , utilize traf6 in their cascade signaling .
tlr are able to activate both the synthesis and release of proinflammatory and osteoclastogenic cytokines from immune cells , leading to bone resorption stimulation .
their involvement in the bone remodeling process provides a further key in the comprehension of the osteoporosis of infectious diseases .
the osteoclast associated receptor ( oscar ) , which belongs to the ig - like receptor family , mediates interactions between ob and oc and is also involved in the regulation of both the adaptive and innate immunity .
it associates with the adaptor molecule fcr subunit , which harbors an immunoreceptor tyrosine - based activation motif ( itam ) critical for calcium signaling activation in the immune system .
also , the itam - harboring adaptor dap12 plays a role in oc differentiation and function .
therefore , receptors such as dap12 and ig - like receptors associated with fcr , initially characterized in myeloid cells and in natural killer lymphocytes , are also involved in rank induced osteoclastogenesis .
tnf induces the expression of oscar and other receptors important for oc differentiation on the surface of monocytoid peripheral blood cells .
for example , cd80/cd86 blocks oc generation by binding to ctla4 , an inhibitory molecule of the monocyte induced t lymphocyte costimulation , which is highly expressed on treg surface .
cathepsin k is expressed in oc and plays a central role in the degradation of bone matrix components , such as type i collagen .
in addition to osteoclastic bone resorption , cathepsin k is also implicated in dendritic cell activation through tlr 9 . moreover
, cathepsin k supports the secretion of il-6 and il-23 , inflammatory cytokines involved in the production of th17 cells , which in turn promote osteoclastic bone resorption .
eph receptors and their associated ligands , expressed by cells found within the bone marrow microenvironment , including ob and oc , are implicated in the regulation of physiological and pathological bone remodeling , but also are central in many other different cellular processes including , in addition to immune regulation , angiogenesis , neuronal development and neoplastic metastatization .
osteoclast semaphorin 4d sustains bone resorption by inhibiting osteoblastogenesis . since sema4d also regulates a variety of immune functions , such as antigen presentation , b lymphocyte activation and chemotaxis of monocytes , it could be regarded as an osteoimmunological mediator .
the matrix glycoprotein osteopontin ( opn ) , produced by different types of cells , including immune cells , oc , endothelial and epithelial cells , increases bone resorption by inducing the expression of the osteoclastic immune receptor cd44 , essential for cell migration , and by directly enhancing oc attachment to bone extracellular matrix ( ecm ) , required for ocp activation . as a consequence of bone resorption , more opn
is further released from the ecm into the bone microenvironment and into the blood , thus amplifying local and systemic osteoclastogenesis .
rankl and cd40l expressed on t cells , apc , stromal cells and ob , activate the cognate receptors rank and cd40 in ocp and ob , respectively .
cd40/cd40l signaling promotes macrophage activation and differentiation , antibody isotype switching , and the development of b cell memory .
cd40l also increases the commitment of msc to the osteoblastic lineage . through cd80/86 signaling in ocp
boh these conditions are mimicked by continuous pth infusion ( cpth ) , whereas daily or intermittent pth injection ( ipth ) , therapeutically employed in several osteoporotic conditions , stimulates bone formation .
pth binds its receptors ( ppr ) on stromal cells , ob , and ocy but also on t cells and macrophages .
the catabolic effect of cpth is mostly mediated by enhanced production of rankl and decreased production of opg by ob and stromal cells .
the pth anabolic effect is mediated by wnt signaling activation : pth increases -catenin levels in ob , promotes lrp6 signaling and decreases the production of sclerostin .
cpth stimulates bone cells and immune cells to release growth factors and cytokines , including il-6 and tnf- , which induce th17 cell differentiation and the production of il-17 , that plays a pivotal role in the pth induced bone loss .
tnf- in turn stimulates oc formation and activity via multiple mechanisms , including increased rankl production .
moreover , tnf- upregulates the expression of cd40 in ob and stromal cells , increasing their sensitivity to cpth and suppressing opg .
bone marrow t cells provide cell surface signals and secrete cytokines that direct the differentiation of mesenchimal progenitors towards ob characterized by a high sensitivity to pth .
therapy with teriparatide , a form of ipth treatment , increases the bone marrow levels of wnt10. bone marrow cd8 + t cells potentiate the anabolic activity of pth by providing wnt10 .
inflammation results in disturbances in the immunoskeletal interface , i.e. the convergence of cells and cytokines that regulate both the immunity that the bone , causing osteoporosis .
the inflammatory cytokines tnf- , il-1 , il-6 and il-17 are crucial in acute and chronic inflammation and strong inducers of bone resorption .
an excessive or abnormal immune activation can induce osteoporosis , as for example in autoimmune diseases , infections and also in senile and postmenopausal osteoporosis .
all these conditions go along with an increased inflammatory background and the presence of rankl producing activated t cells . however , in addition to osteoclastogenic cytokines , there are also cytokines which counteract bone resorption and exert osteoblastogenic properties , resulting in a complex bone remodeling cytokine network .
each cytokine has also pleiotropic functions and it is therefore not surprising that same cytokines can exert different and often contrasting effects depending on the specific context in which they act , the maturation stage of target cells and/or the influence of other cytokines .
for example , the pleiotropic cytokine ifn- exerts anti - osteoclastogenic effects in physiological bone remodeling , by binding to specific oc receptors and inducing traf6 proteosomal degradation with consequent inhibition of the transduction signal mediated by rankl .
however , in postmenopausal osteoporosis , inflammation or infections , the final effect of ifn- is skewed towards bone resorption through t lymphocyte activation and rankl expression .
in fact , ifn- is a powerful stimulator of class ii major histocompatibility complex ( mhcii ) antigen expression on apc , with consequent increased stimulation of t cells through their antigen specific receptor ( tcr ) , inducing further immune activation and production of osteoclastogenic proinflammatory cytokines [ 35 - 40 ] .
a cascade of cytokines drives ocp homing , differentiation and activation . circulating bone marrow produced ocp function as a tank of progenitor cells for several effector cells , in relation to the different cytokines implicated .
the activation of cd8 t cells by oc induces il-2 , il-6 , il-10 and ifn- production .
ocp can also enhance the expression of the suppressor of cytokine signaling ( socs ) .
treg , whose main marker is the transcription factor foxp3 , balance il-17 induced bone resorption closely interacting with oc and expressing ctla-4 , which in turn inhibits oc activity .
endothelial cells , activated by il-1 and tnf- , attract circulating ocp at sites of inflammation where they migrate through high endothelial venules driven by the expression of cell adhesion molecules ( cam ) , such as icam-1 and cd44 .
these cd14 + monocytoid cells , under the stimulation of rankl , become activated bone resorbing oc .
resident tissue macrophages of bone , termed osteal macrophages , are predominantly located adjacent to ob .
osteal macrophages play diverse roles in skeletal homeostasis , their specific functions depending on the macrophage subset considered .
a central function of macrophages is their phagocytic ability . in particular , efferocytosis ( phagocytosis of apoptotic cells ) is a critical process in both clearing dead cells and replacement of progenitor cells to maintain bone homeostasis .
finally , not only the immune system regulates bone remodeling , but also the bone is able to influence the immune system , actively interacting with immune cells . the same bone cells would then be able to influence or even also perform many immune functions , such as cytokine production and antigen presentation [ 46 - 48 ] . in this sense , the bone would be regarded as a sort of expanded immune system .
cytokines secreted by bone cells drive naive t cell differentiation into several lineages , leading to expansion of mature t cell populations that further regulate bone homeostasis .
oc selectively recruit and activate cd8 + t cells expressing cd25 and foxp3 ( oc - induced regulatory cd8 t cells ) . in turn , these cd8 + treg cells suppress bone resorption , decrease inflammatory / osteoclastogenic cytokine production , and stimulate bone formation , creating a regulatory loop : oc and rankl induce treg , and then treg blunt osteoclastic bone resorption .
osteocalcin , expressed on mature bone cells , regulates the production of thymic - seeding t lymphoid progenitors .
they secrete a variety of proinflammatory and immunosuppressive factors . a subset of mesenchimal cells expressing osterix , a marker of bone precursors , regulate the maturation of early b lymphoid precursors by promoting pro - b to pre - b cell transition through insulin - like growth factor 1 ( igf-1 ) production .
skeletal stem cells are also able to recruit and activate neutrophils via the release of il-6 and il-8 , ifn- , gm - csf and mif .
they inhibit b cell proliferation , differentiation , and antibody production , and can also directly inhibit t cell function , rendering them anergic or shifting their phenotype to that of functional regulatory cells .
msc induce macrophages to switch from classically activated proinflammatory ( m1 ) to alternatively activated anti - inflam - matory ( m2 ) phenotype , and inhibit mast cell degranulation attenuating allergic reactions .
msc express active tlr , through which they sense bone microenvironment , recognizing exogenous ( bacterial products ) and endogenous ( heat shock proteins , rna ) danger signals . the common tlr signaling feature is the activation of the nf- b transcription factors implicated in controlling the expression of inflammatory cytokines and cell maturation molecules .
both clinical observations and basic research demonstrated that mediators driving inflammatory processes are also closely involved in bone remodeling .
inflammation and bone turnover share the same mediators , such as cytokines and transcription factors .
various molecules mediating communication between bone cells have been identified and several immunological mediators are involved in this crosstalk .
t lymphocytes resident in the bone marrow are the key immune cells that regulate bone remodeling and responsiveness of bone cells to parathyroid hormone ( pth ) , in physiological and pathological conditions . during inflammatory diseases or in conditions characterized by low - grade systemic inflammation , such as menopause and aging , oc bone resorption is driven by inflammatory cytokines produced by activated t lymphocytes .
however , bone marrow t cells also support bone homeostasis by inducing bone formation via direct interactions with bone cells .
two mechanisms are involved : the binding of t cell costimulatory molecules to their counter receptors on bone cells and their precursors , and the release of cytokines and wnt ligands that activate wnt signaling in osteoblastic cell lineage .
the final effect of t lymphocytes on bone depends on their activation state and their specific phenotype .
the prevailing bone marrow t cells are activated central memory cd8 + lymphocytes , secreting relatively high levels of effector cytokines , mainy tnf-. these cells are abundant in postmenopausal women with osteoporotic fractures .
t helper ( th17 ) cells are capable of stimulating bone resorption and play a pivotal role in the bone loss of inflammatory conditions such as psoriasis , rheumatoid arthritis , periodontal disease , and inflammatory bowel disease .
th17 cells induce osteoclastogenesis by secreting interleukin ( il)-17 , rankl , tnf- , il-1 , and il-6 , along with low levels of ifn-. moreover , il-17 stimulates the release of rankl by ob and ocy and upregulate rank expression on oc .
treg exert anti - osteo - clastogenic activity by producing suppressor cytokines , including il-4 , il-10 , and tgf- .
for example it is interesting to note how even the cells of the immune sytem , mainly activated t and b lymphocytes and dendritic cells , express rankl .
moreover , ran - kl , the principal osteoclastogenic mediator , stimulates bone resorption through the nfatc1 , which is also a crucial factor in the immune system regulation .
rankl , initially regarded as activator of apc by t lymphocytes , also plays an important role in the generation of treg , which suppress the development of cd8 + lymphocytes into cytotoxic cells .
the expression of rankl on t lymphocytes is also central for the differentiation of medullary epithelial cells which are responsible for self - reactive t lymphocyte negative selection in the thymus .
thus , depending on the context in which it acts , rankl can stimulate or suppress immune reactions .
other examples of shared receptor signals are the immunoglobulin ( ig)-like receptors which amplify the nfatc1 signal .
the toll like receptors ( tlr ) , stimulated by pathogen associated molecular patterns ( pamp ) , utilize traf6 in their cascade signaling .
tlr are able to activate both the synthesis and release of proinflammatory and osteoclastogenic cytokines from immune cells , leading to bone resorption stimulation .
their involvement in the bone remodeling process provides a further key in the comprehension of the osteoporosis of infectious diseases .
the osteoclast associated receptor ( oscar ) , which belongs to the ig - like receptor family , mediates interactions between ob and oc and is also involved in the regulation of both the adaptive and innate immunity .
it associates with the adaptor molecule fcr subunit , which harbors an immunoreceptor tyrosine - based activation motif ( itam ) critical for calcium signaling activation in the immune system .
also , the itam - harboring adaptor dap12 plays a role in oc differentiation and function .
therefore , receptors such as dap12 and ig - like receptors associated with fcr , initially characterized in myeloid cells and in natural killer lymphocytes , are also involved in rank induced osteoclastogenesis .
tnf induces the expression of oscar and other receptors important for oc differentiation on the surface of monocytoid peripheral blood cells .
for example , cd80/cd86 blocks oc generation by binding to ctla4 , an inhibitory molecule of the monocyte induced t lymphocyte costimulation , which is highly expressed on treg surface .
cathepsin k is expressed in oc and plays a central role in the degradation of bone matrix components , such as type i collagen .
in addition to osteoclastic bone resorption , cathepsin k is also implicated in dendritic cell activation through tlr 9 . moreover
, cathepsin k supports the secretion of il-6 and il-23 , inflammatory cytokines involved in the production of th17 cells , which in turn promote osteoclastic bone resorption .
eph receptors and their associated ligands , expressed by cells found within the bone marrow microenvironment , including ob and oc , are implicated in the regulation of physiological and pathological bone remodeling , but also are central in many other different cellular processes including , in addition to immune regulation , angiogenesis , neuronal development and neoplastic metastatization .
osteoclast semaphorin 4d sustains bone resorption by inhibiting osteoblastogenesis . since sema4d also regulates a variety of immune functions , such as antigen presentation , b lymphocyte activation and chemotaxis of monocytes , it could be regarded as an osteoimmunological mediator .
the matrix glycoprotein osteopontin ( opn ) , produced by different types of cells , including immune cells , oc , endothelial and epithelial cells , increases bone resorption by inducing the expression of the osteoclastic immune receptor cd44 , essential for cell migration , and by directly enhancing oc attachment to bone extracellular matrix ( ecm ) , required for ocp activation . as a consequence of bone resorption , more opn
is further released from the ecm into the bone microenvironment and into the blood , thus amplifying local and systemic osteoclastogenesis .
rankl and cd40l expressed on t cells , apc , stromal cells and ob , activate the cognate receptors rank and cd40 in ocp and ob , respectively .
cd40/cd40l signaling promotes macrophage activation and differentiation , antibody isotype switching , and the development of b cell memory .
cd40l also increases the commitment of msc to the osteoblastic lineage . through cd80/86 signaling in ocp
boh these conditions are mimicked by continuous pth infusion ( cpth ) , whereas daily or intermittent pth injection ( ipth ) , therapeutically employed in several osteoporotic conditions , stimulates bone formation .
pth binds its receptors ( ppr ) on stromal cells , ob , and ocy but also on t cells and macrophages .
the catabolic effect of cpth is mostly mediated by enhanced production of rankl and decreased production of opg by ob and stromal cells .
the pth anabolic effect is mediated by wnt signaling activation : pth increases -catenin levels in ob , promotes lrp6 signaling and decreases the production of sclerostin .
cpth stimulates bone cells and immune cells to release growth factors and cytokines , including il-6 and tnf- , which induce th17 cell differentiation and the production of il-17 , that plays a pivotal role in the pth induced bone loss .
tnf- in turn stimulates oc formation and activity via multiple mechanisms , including increased rankl production .
moreover , tnf- upregulates the expression of cd40 in ob and stromal cells , increasing their sensitivity to cpth and suppressing opg .
bone marrow t cells provide cell surface signals and secrete cytokines that direct the differentiation of mesenchimal progenitors towards ob characterized by a high sensitivity to pth .
therapy with teriparatide , a form of ipth treatment , increases the bone marrow levels of wnt10. bone marrow cd8 + t cells potentiate the anabolic activity of pth by providing wnt10 .
inflammation results in disturbances in the immunoskeletal interface , i.e. the convergence of cells and cytokines that regulate both the immunity that the bone , causing osteoporosis .
the inflammatory cytokines tnf- , il-1 , il-6 and il-17 are crucial in acute and chronic inflammation and strong inducers of bone resorption .
an excessive or abnormal immune activation can induce osteoporosis , as for example in autoimmune diseases , infections and also in senile and postmenopausal osteoporosis .
all these conditions go along with an increased inflammatory background and the presence of rankl producing activated t cells . however , in addition to osteoclastogenic cytokines , there are also cytokines which counteract bone resorption and exert osteoblastogenic properties , resulting in a complex bone remodeling cytokine network .
each cytokine has also pleiotropic functions and it is therefore not surprising that same cytokines can exert different and often contrasting effects depending on the specific context in which they act , the maturation stage of target cells and/or the influence of other cytokines .
for example , the pleiotropic cytokine ifn- exerts anti - osteoclastogenic effects in physiological bone remodeling , by binding to specific oc receptors and inducing traf6 proteosomal degradation with consequent inhibition of the transduction signal mediated by rankl .
however , in postmenopausal osteoporosis , inflammation or infections , the final effect of ifn- is skewed towards bone resorption through t lymphocyte activation and rankl expression .
in fact , ifn- is a powerful stimulator of class ii major histocompatibility complex ( mhcii ) antigen expression on apc , with consequent increased stimulation of t cells through their antigen specific receptor ( tcr ) , inducing further immune activation and production of osteoclastogenic proinflammatory cytokines [ 35 - 40 ] .
a cascade of cytokines drives ocp homing , differentiation and activation . circulating bone marrow produced ocp function as a tank of progenitor cells for several effector cells , in relation to the different cytokines implicated .
the activation of cd8 t cells by oc induces il-2 , il-6 , il-10 and ifn- production .
ocp can also enhance the expression of the suppressor of cytokine signaling ( socs ) .
treg , whose main marker is the transcription factor foxp3 , balance il-17 induced bone resorption closely interacting with oc and expressing ctla-4 , which in turn inhibits oc activity .
endothelial cells , activated by il-1 and tnf- , attract circulating ocp at sites of inflammation where they migrate through high endothelial venules driven by the expression of cell adhesion molecules ( cam ) , such as icam-1 and cd44 .
these cd14 + monocytoid cells , under the stimulation of rankl , become activated bone resorbing oc .
resident tissue macrophages of bone , termed osteal macrophages , are predominantly located adjacent to ob .
osteal macrophages play diverse roles in skeletal homeostasis , their specific functions depending on the macrophage subset considered .
a central function of macrophages is their phagocytic ability . in particular , efferocytosis ( phagocytosis of apoptotic cells ) is a critical process in both clearing dead cells and replacement of progenitor cells to maintain bone homeostasis .
finally , not only the immune system regulates bone remodeling , but also the bone is able to influence the immune system , actively interacting with immune cells . the same bone cells would then be able to influence or even also perform many immune functions , such as cytokine production and antigen presentation [ 46 - 48 ] . in this sense , the bone would be regarded as a sort of expanded immune system .
cytokines secreted by bone cells drive naive t cell differentiation into several lineages , leading to expansion of mature t cell populations that further regulate bone homeostasis .
oc selectively recruit and activate cd8 + t cells expressing cd25 and foxp3 ( oc - induced regulatory cd8 t cells ) . in turn , these cd8 + treg cells suppress bone resorption , decrease inflammatory / osteoclastogenic cytokine production , and stimulate bone formation , creating a regulatory loop : oc and rankl induce treg , and then treg blunt osteoclastic bone resorption .
osteocalcin , expressed on mature bone cells , regulates the production of thymic - seeding t lymphoid progenitors .
a subset of mesenchimal cells expressing osterix , a marker of bone precursors , regulate the maturation of early b lymphoid precursors by promoting pro - b to pre - b cell transition through insulin - like growth factor 1 ( igf-1 ) production .
skeletal stem cells are also able to recruit and activate neutrophils via the release of il-6 and il-8 , ifn- , gm - csf and mif .
they inhibit b cell proliferation , differentiation , and antibody production , and can also directly inhibit t cell function , rendering them anergic or shifting their phenotype to that of functional regulatory cells .
msc induce macrophages to switch from classically activated proinflammatory ( m1 ) to alternatively activated anti - inflam - matory ( m2 ) phenotype , and inhibit mast cell degranulation attenuating allergic reactions .
msc express active tlr , through which they sense bone microenvironment , recognizing exogenous ( bacterial products ) and endogenous ( heat shock proteins , rna ) danger signals .
the common tlr signaling feature is the activation of the nf- b transcription factors implicated in controlling the expression of inflammatory cytokines and cell maturation molecules .
osteoporosis is a systemic disease of the skeleton , whose main features are loss of bone mass , bone mineral density ( bmd ) decrease and disruption of bone microarchitecture , so the skeleton becomes fragile , exposing patients to increased risk of fractures . aside from senile and postmenopausal osteoporosis , the first recognized types of primary osteoporosis , many other causes of secondary osteoporosis
have been subsequently recognized , for example vitamin d and calcium deficits , lack of sun exposure , immobility , drugs such as cortisone , malabsorption syndromes , endocrine and dismetabolic diseases such as diabetes , disthyroidisms , hypercortisolism , and so on . only later , clinical and experimental findings evidenced a close connection between osteoporosis and immune mediated inflammatory conditions , for example , rheumatoid arthritis ( ra ) and acquired immune deficiency syndrome ( aids ) , and a common inflammatory background has been finally discovered as pathogenetic factor even in conditions of major osteoporotic risk , such as old age and estrogen deficiency [ 57 - 59 ] .
more recently , other unpredictable pathological conditions , such as obesity , are coming out as potential osteoporotic risk factors . even in these cases ,
the main pathogenetic mechanism leading to bone tissue alteration seems to be inflammation . from this point of view osteoporosis
could be therefore regarded as an immune mediated disease in which immune activation , through the induction of cytokine production and inflammation , leads to a remodeling of oc and ob activity and dysregulation of bone turnover with consequent increased bone resorption and osteoporosis .
paradigmatic examples of the link between inflammation and osteoporosis are inflammatory arthritis , mainly ra ( fig .
1 ) . ra is an autoimmune disease that is characterized by inflammation of the synovial joint , leading to severe structural damage and bone destruction .
an increased bone resorption is the main pathogenetic mechanism in both disease progression leading to juxta - articular bone erosions and irreversible joint damage and systemic osteoporosis .
bisphosphonates , drugs used for some time in the therapy of osteoporosis , are potent inhibitors of oc activity both in the primitive and secondary osteoporosis , such as that associated with autoimmune diseases . a decreased bmd in the spine and hip and higher prevalence of osteoporosis have been described in ra patients . in early untreated ra ,
bmd is related to longer symptom duration , the presence of rheumatoid factor ( rf ) and cyclic citrulinated peptide antibodies ( anti - ccp ) , disease activity score , and the presence and progression of joint damage [ 1 , 19 ] .
monoclonal antibodies ( moab ) against various proinflammatory cytokines and their receptors , such as tnf- , are useful in preventing and/or reversing bone erosions as well as systemic osteoporosis .
autoimmune reactions induce rankl expression and subsequent osteoclastogenesis . that the rank/ rankl / opg pathway is central to the osteoporosis pathogenesis
is confirmed by the elevated antiresorptive capacity of denosumab , an anti - rankl moab , utilized in osteoporosis therapy .
activated immune cells at sites of inflammation produce a wide spectrum of proinflammatory and osteoclastogenic cytokines , resulting in bone erosions , osteitis , and peri - inflammatory and systemic bone loss .
local peri - inflammatory bone loss and osteitis occur early and precede and predict erosive bone destruction in ra .
moreover , peri - inflammatory bone formation is impaired , resulting in non - healing of erosions , and this allows a local vicious circle of inflammation between synovitis , osteitis , and local bone loss .
rankl is highly expressed in the ra synovium , and inflammation - mediated bone damage is largely attributable to its abnormally high expression .
in addition to activated t lymphocytes and macrophages , a pivotal role in inducing bone erosions is also played by rankl - expressing b cells , as highlighted by the observation of the therapeutic effect of anti - cd20 antibody in ra .
cd4+t - cells , especially th17 cells , play a prominent role , particularly in the initiation of systemic immune response in ra .
the interaction between immune and mesenchymal cells in joints , including synovial fibroblasts , which are characterized by hyperproliferative and hyperactive properties in response to an inflammatory environment , is of paramount importance in rheumatoid inflammation . in fig .
thus , in the affected joints , hyperplasia of the synovial membrane is characterized by both hyperproliferation of synovial fibroblasts and massive infiltration of inflammatory immune cells , including cd4 + t cells and innate immune cells .
autoimmune diseases , including arthritis , often result from an imbalance between treg cells and th17 cells .
the th17 cells derived from foxp3 + t cells in ra comprise a novel th17 cell subset with a distinct pattern of gene expression and arthritogenic properties .
the fate of plastic foxp3 + t cells may be a key determinant of the treg / th17 balance that is critically involved in the self - tolerance and autoimmunity .
mesenchymal cells are a determinant of the development of ra that links the systemic immune response and the local disorder in the joints .
mesenchymal cells contribute to the th17 mediated chronic inflammation by promoting the migration of th17 cells to the inflamed joint and concomitant increase in il-17 production .
thus , the interaction of immune and mesenchymal cells plays a key role in both the chronic inflammation and bone destruction in ra .
in particular , pathogenetic autoreactive immune cells migrate into joints and activate the mesenchymal cells resident in joint , such as synovial fibroblasts . moreover , since soluble inhibitors of the wnt pathway , such as dkk-1 , produced by synovial fibroblasts , are upregulated by tnf- , antibodies against dkk1 could be able to both promote bone formation and prevent bone erosions in ra .
osteoporosis has long been regarded as simply the consequence of the menopausal estrogen decline . os- the progression of articular erosions is clearly driven by proinflammatory and osteoclastogenic cytokines produced by immune cells in the inflamed joint .
both activated lymphocytes and macrophages stimulate osteoclast differentiation by producing proinflammatory mediators . activated lymphocytes of the synovial pannus overexpress rankl and tnf- that stimulate bone marrow cd11b+ ocp to proliferate and enter the bloodstream where they themselves produce inflammatory factors amplifying inflammation .
activated macrophages in the inflamed joints produce various chemokines which drive the localization of periarticular bone ocp .
the stimulation of osteoclastogenesis induced by the high concentrations of rankl and tnf- results in bone resorption .
these cells do not produce antiosteoclastogenic cytokines , such as ifn- or il4 , while expressing high levels of rankl and secrete il-17 , that in turn stimulates ob , synoviocytes and fibroblasts to express rankl , and induces macrophages to produce proinflammatory cytokines , such as tnf- and il-6 in the synovium amplifying local inflammation .
il-17 also induces the synthesis of enzymes capable of degrading the bone matrix such as matrix metalloproteinases ( mmp ) .
these effects are balanced by treg that inhibit bone destruction by suppressing oc formation through both cell - cell contact and the secretion of inhibitory cytokines such as tgf- , il-4 and il-10 .
teoimmunology , suggesting that immune cells take part in the bone changes typical of menopause , has led to a shift in the concept of osteoporosis , that is currently considered an inflammatory condition .
post - menopausal osteoporosis is a clear example of the mutual influences between immune system , bone and endocrine system . like many other hormones , in addition to specific target organs ( breast and reproductive system )
, estrogens have their receptors also on immune cells and bone , as well as on bone marrow precursors .
( 3 ) shows the effects of estrogen deficiency on cells and molecules involved in bone metabolism .
menopausal estrogen decline leads to proliferation and activation of t cells by increasing mhcii expression on monocytes and apc function and by inhibiting t cell apoptosis .
these effects leads to the expansion of activated t lymphocytes resulting in hyperproduction of inflammatory cytokines and chronic oc stimulation which is responsible for bone loss and increased fracture risk .
maintenance of inflammatory reactions leading to bone resorption and skeletal fragility is also present during senescence and inflammaging ( fig .
4 ) , that is the condition of chronic inflammation characterizing aging , as the result of the immune system s ability to cope with stressors .
inflammaging is now considered the background of a broad range of age - related diseases with an inflammatory pathogenesis .
many of the biological mechanisms implicated in the aging process , such as cell senescence , proinflammatory immune profile , apoptosis and metabolism imbalance , are also implicated in bone remodeling .
also in the absence of overt inflammatory diseases , the heightened catabolic signals induced by inflammation enhance apoptosis of ob and muscle cells , causing both osteoporosis and sarcopenia . during aging
, the lifelong exposure to oxidative stress and chronic antigenic load leads to the loss of the regulatory process which counteracts t cell activation induced bone resorption . in aged people , lipid oxidation mediated by ros
oxidized polyunsaturated fatty acids induce the association of ppar with -catenin and promote its degradation .
oxidized lipids also potentiate oxidative stress , enhance ob apoptosis and inhibit bmp-2 induced ob differentiation .
antioxidant agents seem to have some action on bone remodeling : resveratrol decreases nf - k activation induced by rankl and oc differentiation and also promotes osteogenesis in msc via the sirt1/foxo3 axis stimulation . during senescence , besides the impaired treg function , the number of effector memory cells is increased .
these are senescent cells with proinflammatory properties , secreting several inflammatory cytokines able to influence bone remodeling .
interestingly , this immunological pattern ( accumulation of activated cells and memory / effector lymphocytes secreting proinflammatory cytokines ) characterizing immunosenescence , is also peculiar of other immunological conditions associated with osteoporosis , such as ra , aids , chronic viral infections , etc . .
the already complex cross - talk between bone and immune system is further expanding as they emerge new mediators involved .
interestingly , the scenario of osteoimmunolgy is increasingly including interconnections with other organs and systems , therefore influencing several homeostatic functions in addition to bone turnover and immunity , such as hemopoiesis , metabolic and neuro - endocrine functions .
the crosstalk between skeletal and bone marrow is crucial to hematopoietic stem cell ( hsc ) function and throughout the hemopoiesis .
hsc occupy specific locations in the bone marrow microenvironment , commonly referred to as niches , comprising multiple cell types able to regulate hsc proliferation and differentiation .
hematopoietic and skeletal stem cell homeostasis are closely related : msc progeny express numerous cytokines necessary for hsc maintenance and hematopoiesis , including kit ligand and stromal - derived factor , but also stem and progenitor cells of the hematopoietic system may reciprocally regulate skeletal progenitors by expressing myriad factors associated with skeletogenesis , whose cognate receptors are highly expressed by skeletal stem cells .
interestingly , these latter exhibit receptors to circulating hormones , such as leptin and thyroid - stymulating hormone , suggesting that skeletal stem cells and their progeny may link systemic exocrine regulation to both skeletal and hematopoietic system .
primitive mesenchymal progenitors are more critical for hsc function , whereas lineage - restricted mesenchymal cells control more committed hematopoietic progenitors .
bone microenvironment is therefore a composite of specialized niches providing distinctive functional units to regulate hematopoiesis .
the estrogen deficiency induces a marked increase of inflammatory cytokines and mediators of inflammation , in particular ifn- , m - csf , tnf- , il-1 , il-6 and il-7 , in addition to prostaglandins ( pge ) and reactive oxygen species ( ros ) , which play a driving role in the development of osteoporosis .
of particular interest is the expansion in the peripheral blood from postmenopausal women of two particular lymphocyte subsets , cd3 + cd56 + t lymphocytes , major producers of tnf- , and b220 + igm - b lymphocyte precursors , that under certain stimuli can differentiate into ocp and are strong producers of inflammatory cytokines .
the enhanced tnf- production by activated t cells has a central role in bone loss due to estrogen decline in menopausal women .
the same ifn- , which in some situations could be protective against osteoporosis , during estrogen deficiency has a prevailing osteoclastogenic stimulating action .
the estrogen decline also results in the decrease of opg and tgf- that normally contrast the effects of inflammatory mediators on bone .
the age - related increase of inflammatory cytokines results from a chronic activation of macrophages and memory / effector t cells , in addition to an impaired treg function .
a peculiar finding of immunosenescence is the increased number of senescent memory cells expressing rankl and secreting osteoclastogenic cytokines , mainly tnf- , il-1 , il-6 and il-17 .
these cytokines are able to facilitate ocp expansion which amplify the systemic inflammation by producing further proinflammatory factors able to recruit other inflammatory cells and perpetuating the flogistic vicious cycle .
both the increased transcriptional activity of nf - kb due to genotoxic , inflammatory , and oxidative stresses in aging , and the chronic p53 activation induced by the age - related progressive loss of telomere length , result in impaired ob proliferation and osteoporosis development .
cells of the immune system and bone cells derive from bone marrow precursors and develop in the same bone marrow microenvironment .
hematopoietic and immune cells share same signaling pathways with cells of the bone and their precursors , which surprisingly do not take part in the regulation of immunity and hemopoiesis .
ob , together with msc , are crucial components of the niche of growth of hsc .
ob overexpression of the wnt antagonist dkk1 reduces wnt signaling in hsc and disrupts hsc self - renewal potential .
the wnt antagonist secreted frizzled - related protein 1 ( sfrp1 ) is involved in osteoblastic mediated hsc regulation ; through its regulation of ob , pth controls the hematopoietic niche function , involving crosstalk with wnt signaling .
the upregulation of notch ligand protein jagged-1 ( jag1 ) expression in ob and the increased notch signaling are involved in increasing hsc numbers ; angiopoietin-1 receptor activation on hsc by ob produced angiopoietin-1 promotes strict adhesion of hsc to the niche , inducing quiescence of these cells .
osteopontin , an ob - secreted protein , participates in hsc location and is a negative regulator of their proliferation .
also , ocy derived from ob that become embedded within the bone matrix , are involved in the complex regulation of hemopoiesis through the osteoimmune interface : mainly by the production of sclerostin , they appear to have an inhibitory effect on hsc support .
even oc , as well as activated endothelial cells , are likely involved in the mobilization of hsc by cytokine induced cam expression .
being the only cells capable of bone resorption , in addition to allowing the renewal of the skeleton , they also open the space in the bone marrow for hematopoietic cells .
moreover , osteoclastic bone resorption releases calcium , which attracts and retains calcium sensing receptor expressing hsc at the endosteal region .
macrophages play diverse roles in the bone and marrow . at the sites of bone remodeling ,
a subset of hsc is located in close proximity to megakaryocytes in the bone marrow , where ob undergo rapid expansion in response to the secretion of megakaryocyte - derived mesenchymal growth factors , such as platelet derived growth factor ( pdgf)- , to promote hsc proliferation .
the bone marrow microenvironment can also act as a niche for the onset and progression of neoplastic diseases , including both hematologic malignancies and metastases of solid tumors , mainly breast and prostatic cancer . in multiple myeloma , an osteolytic hematological malignancy characterized by an important skeletal involvement
, neoplastic plasma cells produce a large amount of mediators that induce osteoclastic bone resorption and block the activity of ob .
in addition to osteolytic factors , myeloma cells produce dkk1 , which inhibits obp differentiation by binding to the lrp5/6 coreceptors expressed on their surface . on the other hand ,
the same bone cells produce growth factors and angiogenetic cytokines able to support the development and progression of myeloma , perpetuating a vicious circle of mutual reinforcement .
a promising new field of interest in this regard is the osteo - immune - oncology .
there is in fact a close relationship between immune regulation of bone turnover and tumor growth .
often , cancer cells express rank and in proneoplastic inflammation various cell types express rankl that acts as chemotactic factor favoring the skeletal metastasis . tumor cells in the bone cause activation of osteoclasts that mediate bone resorption and additional growth factor release from the bone matrix , fueling a vicious circle of impaired bone turnover and tumor proliferation ( fig .
not always the tumor associated inflammation is the expression of an immune system that successfully opposes the neoplastic growth , as previously believed , but sometimes some patterns of immune activation can be facilitators of the development of tumors .
then the block of rankl , in addition to inhibiting bone resorption , also decreases tumor growth , enhances apoptosis of malignant cells and diminishes proneoplastic inflammation .
osteal macrophages , as well as macrophages in other tissues , have a role in tumor progression , supporting cancers which preferentially metastasize to the skeleton , in particular breast and prostate cancer .
osteal macrophages expressing cd68 , a phagocytic capacity marker of cells infiltrating metastatic lesions , could facilitate tumor establishment and growth .
tumor - derived pthrp drives myeloid cell recruitment via ob produced ccl2 , which is high in the bone microenvironment and whose levels are associated with poor prognoses in primary breast tumors . as for bone , adipose tissue is a kind of immune tissue and produces immunoregulatory factors .
adipocytes and ob derive from the same msc , as well as visceral adipose tissue macrophages and oc derive from the same hsc .
shared transcription factors regulate the shift between the different cell lines and the subsequent differentiation cascade . by action of peroxisome proliferative
activated receptor gamma ( ppar ) , the principal regulator of adipogenesis , the msc differentiates into adipocytes rather than into ob .
in contrast , the expression of runt - related transcription factor 2 ( runx2 ) , associated with ob differentiation , and osterix , an ob zinc finger
mechanical loading promotes ob differentiation and inhibits adipogenesis by down - regulating ppar or by stimulating a durable -catenin signal .
not surprisingly , ppar agonists such as thiazolidinediones used to increase insulin sensitivity in type 2 diabetes , also increase the risk of osteoporotic fractures .
leptin is a pro - inflammatory adipokine that exerts its actions via central nervous system regulation of feeding behavior , where it promotes satiety and prevents weight gain .
leptin can also directly signal through its receptor expressed on immunocytes , where it induces tnf- and il-6 production by monocytes , chemokines by macrophages , and th1 cytokines from polarized cd4 + t cells .
adiponectin is an anti - inflammatory adipokine whose plasma levels are strongly correlated with insulin sensitivity and glucose tolerance .
it can directly interfere with inflammatory cytokine production in macrophages and can induce expression of the anti - inflammatory cytokine il-10 . tnf- and il-6 inhibit adiponectin production in adipocytes .
adipose tissue produced pro - inflammatory cytokines and adipokines further modulate the activity of oc and ob .
fat tissue , mainly visceral fat tissue , may increase bone resorption through the production of inflammatory cytokines such as il- 6 and tnf- , which stimulate oc activity through the regulation of the rankl / rank / opg pathway .
leptin and adiponectin act on the bone through different signaling pathways with contrasting effects ( table 2 ) .
it promotes adipogenesis and inhibits osteogenesis in response to diet and adiposity by activating jak2/stat3 signaling .
therefore , leptin receptors on skeletal msc function as a sensor of systemic energy homeostasis . various cell populations within the fat tissue can exacerbate the development of the chronic , low - grade inflammation associated with obesity and metabolic dysfunction .
white adipocytes store lipid as triglycerides within unilocular droplets , and are responsive to various stimuli , such as insulin .
brown adipocytes store lipid in multilocular droplets that are quickly catabolized for fuel when the tissue is stimulated .
beige adipocytes , dispersed within white adipose tissue , can dissipate heat , similarly to classical brown adipocytes , when exposed to cold temperatures or after prolonged highfat diet feeding .
visceral fat tissue infiltrating macrophages in the setting of diet - induced obesity , have a pro - inflammatory phenotype which initiates and/or exacerbates the chronic inflammation that contributes to adipocyte dysfunction in obesity .
conversely , in lean humans adipose tissue macrophages may promote tissue remodeling and temper inflammation by secreting anti - inflammatory cytokines .
notwithstanding epidemiological evidence indicates that an increase in body mass index ( bmi ) is related to increased bone mass , probably due to the effects of the mechanical load of the body weight on the skeleton , not always obesity , and mainly the increase in visceral fat mass , has a positive effect on bone .
obesity is associated with increased leptin and decreased adiponectin serum levels . moreover , in the visceral adipose tissue there are activated macrophages producing cytokines . in obese subjects , especially with central obesity , in which the visceral fat is increased , there is a significant increase of several markers of inflammation such as c reactive protein ( crp ) , il-1 , il-6 and tnf- , that can alter the quality of the bone , making it more fragile .
therefore , these new clinical and experimental evidences definitively connect obesity and other related pathological conditions , such as metabolic syndrome , nonalcoholic fatty liver disease ( nafld ) and diabetes , to impaired bone health and fragility fractures [ 90 - 93 ] . in conclusion
, it is currently emerging that adipose tissue , liver , bone and immune system modulate each other through a complex network of interconnected signals .
both adipocytes and ob express opg and rankl and their modulation is influenced by adipokines , sex hormones , redox balance , ppar and liver x receptors ( lxr ) .
osteocalcin , an ob secreted bone matrix noncollagen protein , takes part in calcium metabolism and in bone deposition , as well as in energy homeostasis and glucose metabolism .
fetuin - a , produced by the liver , is involved in the regulation of bone metabolism and insulin action , vascular calcification , neurodegenerative diseases and cancer cell proliferative signaling .
ob lineage cells express receptors for adiponectin , leptin , angiotensin ii , insulin and insulin - like growth factor-1 , able to influence rank / rankl / opg signaling pathway .
interestingly , these hormones are implicated in the pathogenesis of type - ii diabetes , obesity and hypertension , all of which are risk factors for metabolic syndrome .
the development and progression of diabetes - associated osteoporosis are mediated by the interaction between advanced glycation end products ( age ) and receptor of age ( rage ) .
age are the end products of glucose , as well as other sugars , proteins , lipids , and nucleic acids via a non - enzymatic glycosylation reaction , able to bind to multiple membrane receptor proteins , including rage .
age / rage interaction is involved in the pathophysiological processes of many inflammatory and dysmetabolic diseases . in particular ,
age are involved in the development and progression of osteoporosis by inhibiting proliferation and inducing ob apoptosis .
the binding of age to organic bone matrix may also increase the fragility of bones .
autophagy is a metabolic process by which eukaryotic cells degrade and recover damaged macromolecules and organelles into autophagosomes autophagy is upregulated in stressful conditions .
however , excessive autophagy is harmful to cells and leads to damage or massive death of cells .
autophagy deficiency increases oxidative stress levels in ob , decreases bone mineralization and induces ran - kl secretion .
it is well eatablished that several neuroendocrine pathways modulate both immune responses and bone remodeling . in turn
sympathetic nerves produce catecholamines , which are delivered to the bone microenvironment by the blood circulation or by secretion from the nerve endings .
hsc express catecholaminergic receptors , suggesting that they are able to directly respond to signals from the sympathetic nervous system .
adrenergic signaling reduces cxcl12 expression in the bm . affecting maintenance of hsc and the differential lineage commitment .
an association between major depression and osteoporosis has been recognized [ 96 - 99 ] .
the prevalence of low bmd is higher in people with depression than the general population .
interestingly , patients on antidepressant therapy with selective serotonin reuptake inhibitors develop decreased bmd and increased risk of fracture compared to those treated with tricyclic antidepressants such as amitriptyline or patients with untreated depression , who also have a lower bmd compared with healthy controls [ 100 , 101 ] .
neuroendocrine abnormalities of the hypothalamo - pituitary - adrenal ( hpa ) and sympathoadrenal axes are a common finding in depressed patients leading to increased catecholamine turnover and hypersecretion of corticotropin - releasing hormone ( crh ) .
leptin is expressed in the hypothalamus and pituitary gland , where it modulates corticotropin - releasing hormone and acth secretion , probably acting in an autocrine - paracrine manner .
it inhibits steroid - hormone secretion from the adrenal cortex but enhances catecolamine release from the adrenal medulla , activating the sympathoadrenal axis . the neuromodulator serotonin or 5-hydroxy - tryptamine ( 5ht ) , which is an important vasoactive mediator of allergic reactions ,
in addition , it has recently been emerged that proinflammatory cytokines can modulate the central nervous system 5ht signaling , resulting in the conceptualization that 5ht participates in an integrated behavioral response to pathogens and inflammatory events . on the other hand ,
5ht receptor expression on ocy and their precursors is involved in bone metabolism and its mechanoregulation . moreover , serotonin blocks the proliferation of ocp through the suppression of intracellular transcription factor creb , which regulates many genes involved in circadian rhythms in different tissues ( period 1,2,3 and clock genes ) .
there are two anatomically and functionally distinct pools of serotonin : the first one , synthesized through the activity of the enzyme tryptophane - hydroxylase type 2 in the central nervous system , where it functions as neurotransmitter ; the second one is synthesized in the periphery through the activity of the tryptophane - hydroxylase 1 , regulated by the low - density lipoprotein receptor ( ldlr)-related protein-5 ( lrp5 ) .
the circulating serotonin does not exceed the blood brain barrier and is for 95% produced by intestinal enterochromaffin cells in the intestine , where it stimulates peristalsis in response to the meal .
the peripherally produced serotonin acts as a hormone inhibiting bone formation , whereas serotonin produced in the brain functions as a neurotransmitter , enhancing bone formation and limiting bone resorption .
the neurological mechanism of action of serotonin on bone implicates also the interaction with the adipokine leptin , in an integrated homeostatic network with fat tissue and metabolism ( fig .
a portion of 5ht is also produced by the mammary gland , where it acts as an autocrine - paracrine regulator of the epithelial homeostasis exerting antiproliferative and proapoptotic effects .
in the course of pregnancy , lactation and menopause , the local serotonin production increases , contributing to the increased bone resorption typical of these phases of the woman 's life .
small molecules able to specifically inhibit the intestinal tryptophane - hydroxylase and do not cross the blood brain barrier , have recently been proposed for the treatment of osteoporosis . in alzheimer s disease ( ad ) , a neurodegenerative disorder characterized by cortical and cerebrovascular amyloid peptide ( a ) deposits , neurofibrillary tangles , chronic inflammation , and neuronal loss , increased bone fracture rates and reduced bmd are commonly observed , suggesting common denominators between both disorders .
amyloid precursor protein ( app ) is transmembrane protein involved in ad pathogenesis : app gene mutations characterize early - onset ad , and many risk factors or genes associated with late - onset ad appear to affect app trafficking and a production .
rage , acting as an app / a binding partner , is therefore implicated in the pathogenesis of both ad and osteoporosis .
the role of rage in oc maturation and activation is also mediated by its interaction with proinflammatory associated mac-1/2 integrin , the s100 family , and the high mobility group box 1(hmgb1 ) . in particular , hmgb1 is a proin - flammatory cytokine released from activated macro - phages , that promotes rankl - induced oc differentiation in a rage - dependent manner . shared signaling pathways among the complex immunological machineries involved in bone remodeling activate vicious cycles underlying both bone destruction and cancer growth .
the release of growth factors in the skeletal microenvironment as a result of osteolysis induced by oc mediated bone resorption enhances metastases and cancer cell proliferation .
in addition to the hyperproduction of proinflammatory cytokines , rank /rankl signal alterations are central in the pathogenesis of neoplastic osteolysis .
the upregulation of rankl , particularly in myeloma and breast cancer , promotes the growth of neoplastic cells which express rank and protects them from dna damage induced programmed cell death . in this context
, bone cells may represent potential therapeutic targets in the treatment of both secondary neoplastic osteoporosis and the underlying neoplasia .
for example , bisphosphonate treatment of individuals with multiple myeloma reduces osteolytic events and tumor burden as well .
the block of rankl by the monoclonal antibody denosumab , in addition to inhibiting bone resorption , is also useful in reducing tumor growth , in increasing apoptosis of malignant cells and in decreasing the inflammation that supports the neoplasia .
its predominant effect on bone is through the central nervous system : by stimulating specific receptors ( lepr ) on both serotonergic brainstem neurons and the hypothalamic ventromedial nucleus , which interact each other , it increases central sympathetic activity .
inhibitory signals are transmitted through sympathetic fibers from the hypothalamic ventromedial nucleus to 2-adrenergic receptors ( 2-ar ) expressed on ob , suppressing their differentiation and osteocalcin production .
serotonin is synthesized in serotonergic neurons of the central nervous system , exerting various functions in the brain ; it is also synthesized in the gut , mediating different peripheral functions .
it acts on bone cells using three different receptors : through 5ht1b receptors , it negatively regulates bone mass , while it enhances bone formation through 5ht2b and 5ht2c receptors .
the crosstalk between skeletal and bone marrow is crucial to hematopoietic stem cell ( hsc ) function and throughout the hemopoiesis .
hsc occupy specific locations in the bone marrow microenvironment , commonly referred to as niches , comprising multiple cell types able to regulate hsc proliferation and differentiation .
hematopoietic and skeletal stem cell homeostasis are closely related : msc progeny express numerous cytokines necessary for hsc maintenance and hematopoiesis , including kit ligand and stromal - derived factor , but also stem and progenitor cells of the hematopoietic system may reciprocally regulate skeletal progenitors by expressing myriad factors associated with skeletogenesis , whose cognate receptors are highly expressed by skeletal stem cells .
interestingly , these latter exhibit receptors to circulating hormones , such as leptin and thyroid - stymulating hormone , suggesting that skeletal stem cells and their progeny may link systemic exocrine regulation to both skeletal and hematopoietic system .
primitive mesenchymal progenitors are more critical for hsc function , whereas lineage - restricted mesenchymal cells control more committed hematopoietic progenitors .
bone microenvironment is therefore a composite of specialized niches providing distinctive functional units to regulate hematopoiesis .
the estrogen deficiency induces a marked increase of inflammatory cytokines and mediators of inflammation , in particular ifn- , m - csf , tnf- , il-1 , il-6 and il-7 , in addition to prostaglandins ( pge ) and reactive oxygen species ( ros ) , which play a driving role in the development of osteoporosis .
of particular interest is the expansion in the peripheral blood from postmenopausal women of two particular lymphocyte subsets , cd3 + cd56 + t lymphocytes , major producers of tnf- , and b220 + igm - b lymphocyte precursors , that under certain stimuli can differentiate into ocp and are strong producers of inflammatory cytokines .
the enhanced tnf- production by activated t cells has a central role in bone loss due to estrogen decline in menopausal women .
the same ifn- , which in some situations could be protective against osteoporosis , during estrogen deficiency has a prevailing osteoclastogenic stimulating action .
the estrogen decline also results in the decrease of opg and tgf- that normally contrast the effects of inflammatory mediators on bone .
the age - related increase of inflammatory cytokines results from a chronic activation of macrophages and memory / effector t cells , in addition to an impaired treg function .
a peculiar finding of immunosenescence is the increased number of senescent memory cells expressing rankl and secreting osteoclastogenic cytokines , mainly tnf- , il-1 , il-6 and il-17 .
these cytokines are able to facilitate ocp expansion which amplify the systemic inflammation by producing further proinflammatory factors able to recruit other inflammatory cells and perpetuating the flogistic vicious cycle .
both the increased transcriptional activity of nf - kb due to genotoxic , inflammatory , and oxidative stresses in aging , and the chronic p53 activation induced by the age - related progressive loss of telomere length , result in impaired ob proliferation and osteoporosis development .
cells of the immune system and bone cells derive from bone marrow precursors and develop in the same bone marrow microenvironment .
hematopoietic and immune cells share same signaling pathways with cells of the bone and their precursors , which surprisingly do not take part in the regulation of immunity and hemopoiesis .
ob , together with msc , are crucial components of the niche of growth of hsc .
ob overexpression of the wnt antagonist dkk1 reduces wnt signaling in hsc and disrupts hsc self - renewal potential .
the wnt antagonist secreted frizzled - related protein 1 ( sfrp1 ) is involved in osteoblastic mediated hsc regulation ; through its regulation of ob , pth controls the hematopoietic niche function , involving crosstalk with wnt signaling .
the upregulation of notch ligand protein jagged-1 ( jag1 ) expression in ob and the increased notch signaling are involved in increasing hsc numbers ; angiopoietin-1 receptor activation on hsc by ob produced angiopoietin-1 promotes strict adhesion of hsc to the niche , inducing quiescence of these cells .
osteopontin , an ob - secreted protein , participates in hsc location and is a negative regulator of their proliferation .
also , ocy derived from ob that become embedded within the bone matrix , are involved in the complex regulation of hemopoiesis through the osteoimmune interface : mainly by the production of sclerostin , they appear to have an inhibitory effect on hsc support .
even oc , as well as activated endothelial cells , are likely involved in the mobilization of hsc by cytokine induced cam expression .
being the only cells capable of bone resorption , in addition to allowing the renewal of the skeleton , they also open the space in the bone marrow for hematopoietic cells .
moreover , osteoclastic bone resorption releases calcium , which attracts and retains calcium sensing receptor expressing hsc at the endosteal region .
macrophages play diverse roles in the bone and marrow . at the sites of bone remodeling ,
a subset of hsc is located in close proximity to megakaryocytes in the bone marrow , where ob undergo rapid expansion in response to the secretion of megakaryocyte - derived mesenchymal growth factors , such as platelet derived growth factor ( pdgf)- , to promote hsc proliferation .
the bone marrow microenvironment can also act as a niche for the onset and progression of neoplastic diseases , including both hematologic malignancies and metastases of solid tumors , mainly breast and prostatic cancer . in multiple myeloma , an osteolytic hematological malignancy characterized by an important skeletal involvement
, neoplastic plasma cells produce a large amount of mediators that induce osteoclastic bone resorption and block the activity of ob .
in addition to osteolytic factors , myeloma cells produce dkk1 , which inhibits obp differentiation by binding to the lrp5/6 coreceptors expressed on their surface . on the other hand ,
the same bone cells produce growth factors and angiogenetic cytokines able to support the development and progression of myeloma , perpetuating a vicious circle of mutual reinforcement .
a promising new field of interest in this regard is the osteo - immune - oncology .
there is in fact a close relationship between immune regulation of bone turnover and tumor growth .
often , cancer cells express rank and in proneoplastic inflammation various cell types express rankl that acts as chemotactic factor favoring the skeletal metastasis .
tumor cells in the bone cause activation of osteoclasts that mediate bone resorption and additional growth factor release from the bone matrix , fueling a vicious circle of impaired bone turnover and tumor proliferation ( fig . 5 ) . in skeletal metastases ,
not always the tumor associated inflammation is the expression of an immune system that successfully opposes the neoplastic growth , as previously believed , but sometimes some patterns of immune activation can be facilitators of the development of tumors .
then the block of rankl , in addition to inhibiting bone resorption , also decreases tumor growth , enhances apoptosis of malignant cells and diminishes proneoplastic inflammation .
osteal macrophages , as well as macrophages in other tissues , have a role in tumor progression , supporting cancers which preferentially metastasize to the skeleton , in particular breast and prostate cancer .
osteal macrophages expressing cd68 , a phagocytic capacity marker of cells infiltrating metastatic lesions , could facilitate tumor establishment and growth .
tumor - derived pthrp drives myeloid cell recruitment via ob produced ccl2 , which is high in the bone microenvironment and whose levels are associated with poor prognoses in primary breast tumors .
as for bone , adipose tissue is a kind of immune tissue and produces immunoregulatory factors .
adipocytes and ob derive from the same msc , as well as visceral adipose tissue macrophages and oc derive from the same hsc .
shared transcription factors regulate the shift between the different cell lines and the subsequent differentiation cascade . by action of peroxisome proliferative
activated receptor gamma ( ppar ) , the principal regulator of adipogenesis , the msc differentiates into adipocytes rather than into ob .
in contrast , the expression of runt - related transcription factor 2 ( runx2 ) , associated with ob differentiation , and osterix , an ob zinc finger containing transcription factor , shift the equilibrium towards the osteoblastogenesis .
mechanical loading promotes ob differentiation and inhibits adipogenesis by down - regulating ppar or by stimulating a durable -catenin signal .
not surprisingly , ppar agonists such as thiazolidinediones used to increase insulin sensitivity in type 2 diabetes , also increase the risk of osteoporotic fractures .
leptin is a pro - inflammatory adipokine that exerts its actions via central nervous system regulation of feeding behavior , where it promotes satiety and prevents weight gain .
leptin can also directly signal through its receptor expressed on immunocytes , where it induces tnf- and il-6 production by monocytes , chemokines by macrophages , and th1 cytokines from polarized cd4 + t cells .
adiponectin is an anti - inflammatory adipokine whose plasma levels are strongly correlated with insulin sensitivity and glucose tolerance .
it can directly interfere with inflammatory cytokine production in macrophages and can induce expression of the anti - inflammatory cytokine il-10 . tnf- and il-6 inhibit adiponectin production in adipocytes .
adipose tissue produced pro - inflammatory cytokines and adipokines further modulate the activity of oc and ob .
fat tissue , mainly visceral fat tissue , may increase bone resorption through the production of inflammatory cytokines such as il- 6 and tnf- , which stimulate oc activity through the regulation of the rankl / rank / opg pathway .
leptin and adiponectin act on the bone through different signaling pathways with contrasting effects ( table 2 ) .
it promotes adipogenesis and inhibits osteogenesis in response to diet and adiposity by activating jak2/stat3 signaling .
therefore , leptin receptors on skeletal msc function as a sensor of systemic energy homeostasis .
various cell populations within the fat tissue can exacerbate the development of the chronic , low - grade inflammation associated with obesity and metabolic dysfunction .
white adipocytes store lipid as triglycerides within unilocular droplets , and are responsive to various stimuli , such as insulin .
brown adipocytes store lipid in multilocular droplets that are quickly catabolized for fuel when the tissue is stimulated .
beige adipocytes , dispersed within white adipose tissue , can dissipate heat , similarly to classical brown adipocytes , when exposed to cold temperatures or after prolonged highfat diet feeding .
visceral fat tissue infiltrating macrophages in the setting of diet - induced obesity , have a pro - inflammatory phenotype which initiates and/or exacerbates the chronic inflammation that contributes to adipocyte dysfunction in obesity .
conversely , in lean humans adipose tissue macrophages may promote tissue remodeling and temper inflammation by secreting anti - inflammatory cytokines .
notwithstanding epidemiological evidence indicates that an increase in body mass index ( bmi ) is related to increased bone mass , probably due to the effects of the mechanical load of the body weight on the skeleton , not always obesity , and mainly the increase in visceral fat mass , has a positive effect on bone .
obesity is associated with increased leptin and decreased adiponectin serum levels . moreover , in the visceral adipose tissue there are activated macrophages producing cytokines . in obese subjects , especially with central obesity ,
in which the visceral fat is increased , there is a significant increase of several markers of inflammation such as c reactive protein ( crp ) , il-1 , il-6 and tnf- , that can alter the quality of the bone , making it more fragile .
therefore , these new clinical and experimental evidences definitively connect obesity and other related pathological conditions , such as metabolic syndrome , nonalcoholic fatty liver disease ( nafld ) and diabetes , to impaired bone health and fragility fractures [ 90 - 93 ] . in conclusion , it is currently emerging that adipose tissue , liver , bone and immune system modulate each other through a complex network of interconnected signals .
both adipocytes and ob express opg and rankl and their modulation is influenced by adipokines , sex hormones , redox balance , ppar and liver x receptors ( lxr ) .
osteocalcin , an ob secreted bone matrix noncollagen protein , takes part in calcium metabolism and in bone deposition , as well as in energy homeostasis and glucose metabolism .
fetuin - a , produced by the liver , is involved in the regulation of bone metabolism and insulin action , vascular calcification , neurodegenerative diseases and cancer cell proliferative signaling .
ob lineage cells express receptors for adiponectin , leptin , angiotensin ii , insulin and insulin - like growth factor-1 , able to influence rank / rankl / opg signaling pathway .
interestingly , these hormones are implicated in the pathogenesis of type - ii diabetes , obesity and hypertension , all of which are risk factors for metabolic syndrome .
the development and progression of diabetes - associated osteoporosis are mediated by the interaction between advanced glycation end products ( age ) and receptor of age ( rage ) .
age are the end products of glucose , as well as other sugars , proteins , lipids , and nucleic acids via a non - enzymatic glycosylation reaction , able to bind to multiple membrane receptor proteins , including rage .
age / rage interaction is involved in the pathophysiological processes of many inflammatory and dysmetabolic diseases .
in particular , age are involved in the development and progression of osteoporosis by inhibiting proliferation and inducing ob apoptosis .
the binding of age to organic bone matrix may also increase the fragility of bones .
autophagy is a metabolic process by which eukaryotic cells degrade and recover damaged macromolecules and organelles into autophagosomes autophagy is upregulated in stressful conditions .
however , excessive autophagy is harmful to cells and leads to damage or massive death of cells .
autophagy deficiency increases oxidative stress levels in ob , decreases bone mineralization and induces ran - kl secretion .
it is well eatablished that several neuroendocrine pathways modulate both immune responses and bone remodeling . in turn
sympathetic nerves produce catecholamines , which are delivered to the bone microenvironment by the blood circulation or by secretion from the nerve endings .
hsc express catecholaminergic receptors , suggesting that they are able to directly respond to signals from the sympathetic nervous system .
adrenergic signaling reduces cxcl12 expression in the bm . affecting maintenance of hsc and the differential lineage commitment .
an association between major depression and osteoporosis has been recognized [ 96 - 99 ] .
the prevalence of low bmd is higher in people with depression than the general population .
interestingly , patients on antidepressant therapy with selective serotonin reuptake inhibitors develop decreased bmd and increased risk of fracture compared to those treated with tricyclic antidepressants such as amitriptyline or patients with untreated depression , who also have a lower bmd compared with healthy controls [ 100 , 101 ] .
neuroendocrine abnormalities of the hypothalamo - pituitary - adrenal ( hpa ) and sympathoadrenal axes are a common finding in depressed patients leading to increased catecholamine turnover and hypersecretion of corticotropin - releasing hormone ( crh ) .
leptin is expressed in the hypothalamus and pituitary gland , where it modulates corticotropin - releasing hormone and acth secretion , probably acting in an autocrine - paracrine manner .
it inhibits steroid - hormone secretion from the adrenal cortex but enhances catecolamine release from the adrenal medulla , activating the sympathoadrenal axis .
the neuromodulator serotonin or 5-hydroxy - tryptamine ( 5ht ) , which is an important vasoactive mediator of allergic reactions , is also likely involved in interactions between the central nervous and immune systems .
in addition , it has recently been emerged that proinflammatory cytokines can modulate the central nervous system 5ht signaling , resulting in the conceptualization that 5ht participates in an integrated behavioral response to pathogens and inflammatory events . on the other hand ,
5ht receptor expression on ocy and their precursors is involved in bone metabolism and its mechanoregulation . moreover , serotonin blocks the proliferation of ocp through the suppression of intracellular transcription factor creb , which regulates many genes involved in circadian rhythms in different tissues ( period 1,2,3 and clock genes ) .
there are two anatomically and functionally distinct pools of serotonin : the first one , synthesized through the activity of the enzyme tryptophane - hydroxylase type 2 in the central nervous system , where it functions as neurotransmitter ; the second one is synthesized in the periphery through the activity of the tryptophane - hydroxylase 1 , regulated by the low - density lipoprotein receptor ( ldlr)-related protein-5 ( lrp5 ) .
the circulating serotonin does not exceed the blood brain barrier and is for 95% produced by intestinal enterochromaffin cells in the intestine , where it stimulates peristalsis in response to the meal .
the peripherally produced serotonin acts as a hormone inhibiting bone formation , whereas serotonin produced in the brain functions as a neurotransmitter , enhancing bone formation and limiting bone resorption .
the neurological mechanism of action of serotonin on bone implicates also the interaction with the adipokine leptin , in an integrated homeostatic network with fat tissue and metabolism ( fig .
a portion of 5ht is also produced by the mammary gland , where it acts as an autocrine - paracrine regulator of the epithelial homeostasis exerting antiproliferative and proapoptotic effects .
in the course of pregnancy , lactation and menopause , the local serotonin production increases , contributing to the increased bone resorption typical of these phases of the woman 's life .
small molecules able to specifically inhibit the intestinal tryptophane - hydroxylase and do not cross the blood brain barrier , have recently been proposed for the treatment of osteoporosis . in alzheimer s disease ( ad ) , a neurodegenerative disorder characterized by cortical and cerebrovascular amyloid peptide ( a ) deposits , neurofibrillary tangles , chronic inflammation , and neuronal loss , increased bone fracture rates and reduced bmd are commonly observed , suggesting common denominators between both disorders .
amyloid precursor protein ( app ) is transmembrane protein involved in ad pathogenesis : app gene mutations characterize early - onset ad , and many risk factors or genes associated with late - onset ad appear to affect app trafficking and a production .
rage , acting as an app / a binding partner , is therefore implicated in the pathogenesis of both ad and osteoporosis .
the role of rage in oc maturation and activation is also mediated by its interaction with proinflammatory associated mac-1/2 integrin , the s100 family , and the high mobility group box 1(hmgb1 ) . in particular , hmgb1 is a proin - flammatory cytokine released from activated macro - phages , that promotes rankl - induced oc differentiation in a rage - dependent manner .
shared signaling pathways among the complex immunological machineries involved in bone remodeling activate vicious cycles underlying both bone destruction and cancer growth .
the release of growth factors in the skeletal microenvironment as a result of osteolysis induced by oc mediated bone resorption enhances metastases and cancer cell proliferation .
in addition to the hyperproduction of proinflammatory cytokines , rank /rankl signal alterations are central in the pathogenesis of neoplastic osteolysis . the upregulation of rankl , particularly in myeloma and breast cancer , promotes the growth of neoplastic cells which express rank and protects them from dna damage induced programmed cell death . in this context
, bone cells may represent potential therapeutic targets in the treatment of both secondary neoplastic osteoporosis and the underlying neoplasia .
for example , bisphosphonate treatment of individuals with multiple myeloma reduces osteolytic events and tumor burden as well .
the block of rankl by the monoclonal antibody denosumab , in addition to inhibiting bone resorption , is also useful in reducing tumor growth , in increasing apoptosis of malignant cells and in decreasing the inflammation that supports the neoplasia .
its predominant effect on bone is through the central nervous system : by stimulating specific receptors ( lepr ) on both serotonergic brainstem neurons and the hypothalamic ventromedial nucleus , which interact each other , it increases central sympathetic activity .
inhibitory signals are transmitted through sympathetic fibers from the hypothalamic ventromedial nucleus to 2-adrenergic receptors ( 2-ar ) expressed on ob , suppressing their differentiation and osteocalcin production .
serotonin is synthesized in serotonergic neurons of the central nervous system , exerting various functions in the brain ; it is also synthesized in the gut , mediating different peripheral functions .
it acts on bone cells using three different receptors : through 5ht1b receptors , it negatively regulates bone mass , while it enhances bone formation through 5ht2b and 5ht2c receptors .
immune system and skeletal system interact with each other both in physiological and pathological conditions .
considerable progress has been made in clarifying the crosstalk between bone and immune system that occurs in a complex and dynamic bone microenvironment . a central role in this crosstalk
osteoimmunology therefore represents a new approach to studying osteoporosis that in the past was not considered an inflammatory condition .
moreover , the discoveries of the existence of the immunoskeletal interface has also highlighted interesting repercussions for a wide range of pathological conditions beyond osteoporosis , including infections , autoimmune diseases , and neoplasia , in which same pathogenetic pathways are shared .
osteoporosis could be therefore considered as a systemic model of integrated signaling pathways and cytokines working in a cooperative fashion .
further important research horizons are opened with the extension of the discoveries of osteoimmunology and the disclosure of the immunoskeletal interface , whose practical implications may provide novel therapies for diseases other than osteoporosis , by targeting specific transcription factors , cytokines and their receptors . the correct understanding and decoding of the complex language
through which immune system and bone communicate , although still in its dawn , is the essential requirement for the identification of such potentially useful therapeutic targets for both osteoporosis and other correlated inflammatory conditions , which share same mediators and signaling pathways . | abstract : objectiveosteoimmunology investigates interactions between skeleton and immune system . in the light of recent discoveries in this field , a new reading register of osteoporosis is actually emerging , in which bone and immune cells are strictly interconnected .
osteoporosis could therefore be considered a chronic immune mediated disease which shares with other age related disorders a common inflammatory background . here
, we highlight these recent discoveries and the new landscape that is emerging.methodextensive literature search in pubmed central.resultswhile the inflammatory nature of osteoporosis has been clearly recognized , other interesting aspects of osteoimmunology are currently emerging .
in addition , mounting evidence indicates that the immunoskeletal interface is involved in the regulation of important body functions beyond bone remodeling .
bone cells take part with cells of the immune system in various immunological functions , configuring a real expanded immune system , and are therefore variously involved not only as target but also as main actors in various pathological conditions affecting primarily the immune system , such as autoimmunity and immune deficiencies , as well as in aging , menopause and other diseases sharing an inflammatory background.conclusionthe review highlights the complexity of interwoven pathways and shared mechanisms of the crosstalk between the immune and bone systems .
more interestingly , the interdisciplinary field of osteoimmunology is now expanding beyond bone and immune cells , defining new homeostatic networks in which other organs and systems are functionally interconnected .
therefore , the correct skeletal integrity maintenance may be also relevant to other functions outside its involvement in bone mineral homeostasis , hemopoiesis and immunity . | [
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there appears to have been consensus in the past decades in classifying systemic sclerosis ( ssc ) according to extension of skin involvement as limited and diffuse , using the elbows and knees as limits to distinguish between them .
however , although this has been used to dissect two more or less distinct clinical subsets , there are patients who do not fit this classification and several others have been proposed [ 1 , 2 ] .
the growing demonstration that autoantibodies specific for ssc such as anticentromere , anti - scl-70 ( anti - topoisomerase 1 ) , and more recently a variety of antinucleolar antibodies , particularly anti - rna polymerase 3 , correlate with these subsets and/or visceral manifestations has led to them being used to
predict clinical subsets in early disease and also raise awareness for the possibility of certain organ involvement ( anti - scl-70 and interstitial lung disease [ 3 , 4 ] , anticentromere associated with digital ulcers , debatably pulmonary hypertension , and anti - rna polymerase 3 with renal crisis ) .
decades ago , barnett classified ssc as type 1 ( only sclerodactyly ) , type 2 ( acrosclerosis - distal but may reach up to elbows and/or knees plus face ) , and type 3 ( diffuse skin involvement ) ( figure 1 ) .
patients with type 2 had an intermediate degree of both skin and organ involvement compared to type 1 ( less ) and type 3 ( more ) [ 810 ] .
this classification by barnett was extensively discussed in an editorial by masi many years later .
the division into three categories according to extension of skin involvement was not agreed to by others , who could not find real differences between what we could call types 1 and 2 as determined by barnett [ 1 , 2 ] . a similar classification but this time with 4 categories , proposed by giordano et al .
simultaneously , as reasonable stress was laid on early disease detection , the extent of cutaneous involvement was perhaps not considered so relevant , particularly as opposed to the autoantibodies as subset identifiers . however
, truth is that many patients present with evolving disease , and all of ssc specific antibodies are not widely available in many parts of the world , the best example being anti - rna polymerase .
many years ago but with a small number of patients , we noted that the limited subgroup could be , indeed , separated clinically as barnett had suggested according to skin involvement into patients with only fingers , which we proposed to call crest , and those with skin distal to elbows and knees but proximal to mcp or mtp joints , which we proposed to call creat ( a instead of s for acrosclerosis ) . in that report , crest patients had more anticentromere antibodies than those with creat and the presence of anti - scl-70 occurred more frequently in the patients with creat than those with crest .
small numbers did not allow for detection of clinical differences . over the past decades ,
many of the larger series [ 416 ] and particularly the eustar database , one of the largest registries , have not differentiated subsets within the limited form ( scleroderma sine scleroderma excluded ) .
very recently however , in a very large series from a single center followed for years , the hopkins group emphasized just this , showing differences between the two limited groups and stressing the higher prevalence of lung disease and anti - scl-70 antibodies in the type 2 ( barnett ) or intermediate form when compared with type 1 , a behavior more similar to the diffuse form , and similar to what we had supported and barnett proposed years ago .
their conclusion was that dividing into limited and diffuse as we do now left out an intermediate form with different clinical and serological characteristics .
since over the years it was our feeling that this subsetting was clinically useful , we always registered extension of skin involvement in our patients , particularly identifying those with intermediate form within the lssc .
we therefore decided to examine the clinical and serologic characteristics of our patients with limited disease seen over the last decade to see if we could find differences within them according to the degree of skin involvement .
rheumatology section database , patients with icd 9 code 710.1 ( scleroderma ) in the inpatient hospital database , patients with the item : scleroderma , crest , or other synonyms as registered in the hospital 's electronic clinical history ; and laboratory database : patients with positive anticentromere , antinucleolar , or anti - scl-70 results .
all medical records so identified were then manually reviewed to confirm diagnosis and obtain demographic data such as date of onset , clinical characteristics , and serologic profile . only cases fulfilling acr 1980 criteria were included and were classified as diffuse or limited according to leroy 's criteria .
this difference in distribution was established considering the involvement of skin at its maximum extension at any point in the disease course . within the limited subset , they were separated into sclerodactyly ( only fingers ) and acrosclerosis ( fingers and up to elbows and/or knees , face ) ( barnett 's types 1 and 2 ) .
ssc clinical manifestations were considered to be present if predefined criteria were met during the course of the illness .
organ involvement definitions were the following : ( 1 ) upper gastrointestinal tract ( one or more of the following : manometry with esophageal dysmotility , esophagram with gastroesophagic reflux or peristaltic alterations , or upper endoscopy with esophagitis , ( 2 ) pulmonary hypertension ( ph ) : echocardiogram with estimated pulmonary systolic artery pressure equal to or greater than 40 mmhg or right heart catheterization with mean pulmonary artery pressure at rest over 25 mmhg , ( 3 ) interstitial lung disease ( ild ) : pulmonary interstitial disease observed in high resolution computerized tomography ( hrct ) or pulmonary function tests with vital forced capacity ( vfc ) lower than 70% of the expected and/or carbon monoxide lung diffusion ( dlco ) test under 80% of the expected , ( 4 ) echocardiographic alterations ( aside from ph ) : left or right ventricular diastolic dysfunction in absence of arterial hypertension or pulmonary hypertension , respectively , or pericardial effusion , ( 5 ) digital ulcers : active digital ulcers or pitting scars confirmed by a physician , ( 6 ) renal involvement : history of scleroderma renal crisis ( abrupt onset of accelerated arterial hypertension and/or rapidly progressive renal failure ) .
laboratory detection methods were indirect immunofluorescence on hep-2 cells ( antinuclear antibodies , antinucleolar , and anticentromere ) .
chi - square analysis was used to determine significant differences between sets of categorical data and fisher 's exact test when appropriate .
two hundred and thirty four ssc patients ( 216 females ) fulfilled the established criteria .
female / male ratio was 12 : 1 ; 24% had diffuse ssc and 76% limited ( 64% sclerodactyly and 12% acrosclerosis ) .
ten - year survival rate was 80% for limited and 70% for diffuse variants , respectively ( hr : 0.88 , 95% ci : 0.71.1 ) .
anti - scl-70 was present in 16% , anticentromere in 53% , and nucleolar ana in 7% of overall patients .
several characteristics in the acrosclerosis ( type 2 ) group were more similar to the diffuse patients than those with type 1 ( sclerodactyly ) . in patients with acrosclerosis , duration of raynaud 's was shorter , and they had significantly more anti - scl-70 and less anticentromere antibodies than those with type 1 .
in particular , interstitial lung disease ( ild ) was significantly more prevalent in type 2 group and similar to type 3 .
comparisons between patients with acrosclerosis and diffuse disease are presented in table 2 , showing no differences in clinical manifestations . as described elsewhere ,
autoantibodies were associated with visceral involvement and also with clinical subset . in univariate analysis ,
anticentromere antibodies were associated with pulmonary hypertension , or of 8.25 ( ci 1.935.7 ) , and inversely correlated with ild ( or 0.18 , ci 0.110.29 ) .
they were also associated with limited disease , or 34.4 ( ci 10.2116.6 ) . when performing multivariate analysis adjusting by disease subset , association between anticentromere and pulmonary hypertension was lost .
all of the patients with ph had lssc ( 11 with sclerodactyly and 1 with acrosclerosis ) except for one patient with diffuse disease with anticentromere antibodies . in summary ,
in multivariate analysis , both anti - scl-70 ( or 5.2 , ci 1.517.6 , p = 0.08 ) and diffuse disease ( or 4.1 , ci 1.213.5 , p = 0.021 ) were associated with ild .
these findings are very similar to those recently described by cottrell et al . within the
limited patients , dissecting between what could be barnett 's type 1 and 2 subsets .
our results support the initial description by barnett et al . that there is an intermediate form of ssc between the
some of these patients , albeit with limited scleroderma because skin involvement does not exceed elbows and/or knees , have a clinical behavior which can be described as intermediate between the strictly limited to fingers patients and those with diffuse disease . in particular , a sort of gradient from milder to more severe disease was confirmed in our patients , as suggested by barnett many years ago .
this was also shown by the hopkins group in a much larger number of patients . indeed , in type 2 as defined by barnett , serology may be more similar to the diffuse type and different from type 1
. the gradient is also reflected by the accompanying antibodies which further define visceral involvement such as pulmonary hypertension and interstitial lung disease .
these results appear to confirm that extension of skin involvement within limited ssc may identify two different subsets with clinical and serologic characteristics .
autoantibodies , in many cases present years prior to diagnosis and established skin disease , play an essential role here as predictors of clinical subsets and visceral involvement . however , some of these are not widely available .
furthermore , many patients present with established disease , although early , and in these a clinical approach contemplating extent of skin involvement coupled with the classic autoantibodies may indeed be useful and support a division within the limited form which may have useful clinical implications . a retrospective review of data in the large registries trying to document skin extension may or may not confirm this .
the problem may arise in the fact that since the extension of skin involvement within limited disease was not considered important , this may not have been adequately registered .
our smaller series completely agrees with the data shown by the hopkins group with a very large number of patients .
we believe identifying these differences within limited ssc is useful and resuscitating the intermediate form or barnett type 2 within limited ssc may contribute to a better clinical assessment of systemic sclerosis . |
objectives . to examine the characteristics of our patients with limited systemic sclerosis ( lssc ) for differences between barnett type 1 ( sclerodactyly only ) and type 2 or intermediate ( acrosclerosis - distal but may reach up to elbows and/or knees plus face ) subsets . methods .
records of patients between january 1 , 2000 , and december 31 , 2011 , with ssc or those with anti - scl-70 , anticentromere , or antinucleolar antibodies were reviewed . only cases fulfilling acr 1980 criteria were included and classified as diffuse or limited according to leroy 's criteria .
limited ssc was separated into sclerodactyly and acrosclerosis ( barnett 's types 1 and 2 ) . results . 234 ssc patients ( 216 females ) fulfilled criteria .
female / male ratio was 12 : 1 ; 24% had dssc and 76% lssc ( 64% type 1 and 12% type 2 ) .
total follow - up was 688 patient - years .
within lssc , the type 2 group had significantly shorter duration of raynaud 's and more anti - scl-70 and less anticentromere antibodies .
in particular , interstitial lung disease ( ild ) was significantly more prevalent in type 2 group and similar to type 3 . conclusions . these results appear to confirm that extension of skin involvement within limited ssc may identify two different subsets with clinical and serologic characteristics . | [
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] |
common failure of the root canal obturation process is because of the presence of gaps and porosities at the sealer / dentin interface .
several studies have shown that filled root canals can allow the re - colonization of micro - organisms .
the presence of micro - organisms and their products in the treated root canal can led to failure of the root canal treatment and the necessity of retreatment .
the analysis of the dentin / sealer interface allows the determination of which materials and filling techniques could obturate the root canals with less gaps and voids .
several microscopy techniques are currently used to evaluate the sealer / dentin interface , including stereomicroscopy , scanning electron microscopy ( sem ) , transmission electron microscopy , and confocal laser scanning microscopy ( clsm ) . in comparison to conventional sem , clsm has the advantage of providing detailed information about the presence and distribution of sealers or dental adhesives inside dentinal tubules in the total circumference of the root canal walls at relative low magnification as 100x through the use of fluorescent rhodamine marked sealers .
placement and activation of a sealer into the root canal system should be done in a manner which is predictable and completely covers the dentin walls . accepted
means of sealer placement include the use of endodontic files or reamers , lentulo spirals , gutta - percha cones , ultrasonic files , and counter - clockwise motion of rotary systems .
very few studies have been done to evaluate the efficacy of different methods of sealer placement and activation effectively .
mta fillapex is a sealer that is composed of mta and has excellent flow , radiopacity , easy handling , working time , and low solubility . because of its suitable physicochemical properties and excellent biocompatibility and bioactivity ,
hence , this study was planned to evaluate percentage and the depth of dentinal tubule sealer penetration of mta fillapex when agitated with three different techniques and to compare it with ah plus using clsm as the evaluative tool .
sixty teeth with single canal and free of cracks , caries , resorption , calcification , previous endodontic treatment , and less than 10- root curvature were selected and stored in distilled water until use . for standardization of the root length ( 10 mm )
, the crowns were resected with a diamond disc in a slow speed straight handpiece under constant water cooling .
the working length was determined by inserting # 15 k - file ( dentsply maillefer ) into the canal until it was just seen at the apical foramen and then 0.5 mm was subtracted from this length .
the roots were instrumented by using the protaper universal root canal files ( dentsply maillefer ) in a sequential manner from s1 till f5 .
canals were irrigated between files with 2 ml of 3% naocl ( sree rayalaseema alkalies and allies chemicals limited , india ) . to eliminate the smear layer 2 ml of 17% ethylenediaminetetraacetic acid ( edta ) ( ph 7.7 ) for 3 min was used , followed by a final rinse of 2 ml distilled water .
the roots were randomly divided into three groups on the basis of sealer activation technique utilized : g1 : ultrasonic ( woodpecker dte - d5 ultrasonic scaler , china ) ; g2 : lentulo spiral ( dentsply , maillefer ) ; g3 : counter - clockwise motion ( x smart , densply , maillefer , ballaigues , switzerland ) .
each group was further divided into two subgroups on the basis of type of sealer .
subgroup a utilized ah plus sealer while subgroup m utilized mta fillapex sealer . ah plus sealer and mta fillapex sealer were mixed according to the manufacturer instructions and to allow analysis under the clsm , each sealer was labelled with rhodamine b ( mayor diagnostics , mumbai , india ) to an approximate concentration of 0.1%(by weight ) .
group 1 ( g1 ) : the ultrasonic unit ( woodpecker dte - d5 ultrasonic scaler , china ) was used in endo mode with a satelec ultrasonic endodontic tip k15 sonofile ( dentsply tulsa ) for activation . the file was inserted 2 mm short of the working length inside the canal and was ultrasonically activated for 20 seconds .
gutta - percha was compacted 1 mm below the canal orifice and the teeth were sealed with cavit ( 3 m , espe ) . in g1a ah plus sealer and in g1 m , mta fillapex sealer was used .
group 2 ( g2 ) : a size 30 lentulo spiral ( dentsply , maillefer ) was selected that would not bind in the prepared canal and that would reach the prepared working length . the lentulo spiral was rotated at speed of 300 rpm keeping the instrument 2 mm from apex for 20 seconds .
thereafter , the obturation of canal was conducted as described for g1 . in g2a ah plus sealer and in g2 m , mta fillapex sealer was used .
group 3 ( g3 ) : f1 protaper file attached in handpiece of endodontic micromotor ( x - smart , dentsply tulsa ) was kept 2 mm short of apex and rotated at 300 rpm in reverse mode for 20 seconds .
thereafter , the obturation of canal was conducted as described for g1 . in g3a ah plus sealer and in g3 m , mta fillapex sealer was used .
the specimens were kept in an incubator at 37c and 100% humidity for 2 days .
each root was sectioned at 90- to the long axis by using diamond disc removing two , 1 mm sections at 3 mm and 6 mm from the apex .
coronal surface of each section was polished with sand paper ( politriz , arotec , cotia , sp , brazil ) .
the dentin segments were examined on a confocal microscope ( olympus fluoview fv 1000 ) .
the respective absorption and emission wave lengths for the rhodomine b were 540 nm and 590 nm .
dentin samples were analyzed using the 10x lens . to calculate the percentage of sealer penetration around the root canal , first each image was imported into the iob software and the circumference of root canal measured using its ruler tool .
next , areas along the canal walls in which the sealer penetrated into dentinal tubules were outlined and measured using the same method [ figure 1 ] .
subsequently , the percentage of root canal sealer penetration in that section was established . to determine the maximum depth of penetration , the point of deepest penetration was measured from the canal wall to the maximum depth of penetration [ figure 2 ] .
the effects of sealer agitation techniques and type of sealer on depth and percentage of sealer penetration were analyzed , by performing nonparametric kruskal - wallis for overall analysis , and a series of mann - whitney u tests for pairwise comparison using statistical package of social sciences ( spss ) statistics 20 software .
confocal laser scanning microscopic photograph showing calculation of percentage of penetration of sealer in the dentinal tubules ( original magnification 10 ) confocal laser scanning microscopic photograph showing calculation of depth of penetration of sealer in the dentinal tubules ( original magnification 10 )
sixty teeth with single canal and free of cracks , caries , resorption , calcification , previous endodontic treatment , and less than 10- root curvature were selected and stored in distilled water until use .
for standardization of the root length ( 10 mm ) , the crowns were resected with a diamond disc in a slow speed straight handpiece under constant water cooling .
the working length was determined by inserting # 15 k - file ( dentsply maillefer ) into the canal until it was just seen at the apical foramen and then 0.5 mm was subtracted from this length .
the roots were instrumented by using the protaper universal root canal files ( dentsply maillefer ) in a sequential manner from s1 till f5 .
canals were irrigated between files with 2 ml of 3% naocl ( sree rayalaseema alkalies and allies chemicals limited , india ) . to eliminate the smear layer 2 ml of 17% ethylenediaminetetraacetic acid ( edta ) ( ph 7.7 ) for
3 min was used , followed by a final rinse of 2 ml distilled water .
the roots were randomly divided into three groups on the basis of sealer activation technique utilized : g1 : ultrasonic ( woodpecker dte - d5 ultrasonic scaler , china ) ; g2 : lentulo spiral ( dentsply , maillefer ) ; g3 : counter - clockwise motion ( x smart , densply , maillefer , ballaigues , switzerland ) .
each group was further divided into two subgroups on the basis of type of sealer .
ah plus sealer and mta fillapex sealer were mixed according to the manufacturer instructions and to allow analysis under the clsm , each sealer was labelled with rhodamine b ( mayor diagnostics , mumbai , india ) to an approximate concentration of 0.1%(by weight ) .
group 1 ( g1 ) : the ultrasonic unit ( woodpecker dte - d5 ultrasonic scaler , china ) was used in endo mode with a satelec ultrasonic endodontic tip k15 sonofile ( dentsply tulsa ) for activation . the file was inserted 2 mm short of the working length inside the canal and was ultrasonically activated for 20 seconds . canal was obturated with protaper f5 gutta - percha cone .
gutta - percha was compacted 1 mm below the canal orifice and the teeth were sealed with cavit ( 3 m , espe ) . in g1a ah plus sealer and in g1 m , mta fillapex sealer was used .
group 2 ( g2 ) : a size 30 lentulo spiral ( dentsply , maillefer ) was selected that would not bind in the prepared canal and that would reach the prepared working length . the lentulo spiral was rotated at speed of 300 rpm keeping the instrument 2 mm from apex for 20 seconds .
thereafter , the obturation of canal was conducted as described for g1 . in g2a ah plus sealer and in g2 m , mta fillapex sealer was used .
group 3 ( g3 ) : f1 protaper file attached in handpiece of endodontic micromotor ( x - smart , dentsply tulsa ) was kept 2 mm short of apex and rotated at 300 rpm in reverse mode for 20 seconds .
thereafter , the obturation of canal was conducted as described for g1 . in g3a ah plus sealer and in g3 m , mta fillapex sealer was used .
the specimens were kept in an incubator at 37c and 100% humidity for 2 days .
each root was sectioned at 90- to the long axis by using diamond disc removing two , 1 mm sections at 3 mm and 6 mm from the apex .
coronal surface of each section was polished with sand paper ( politriz , arotec , cotia , sp , brazil ) .
the dentin segments were examined on a confocal microscope ( olympus fluoview fv 1000 ) .
the respective absorption and emission wave lengths for the rhodomine b were 540 nm and 590 nm .
dentin samples were analyzed using the 10x lens . to calculate the percentage of sealer penetration around the root canal , first each image was imported into the iob software and the circumference of root canal measured using its ruler tool .
next , areas along the canal walls in which the sealer penetrated into dentinal tubules were outlined and measured using the same method [ figure 1 ] .
subsequently , the percentage of root canal sealer penetration in that section was established . to determine the maximum depth of penetration , the point of deepest penetration was measured from the canal wall to the maximum depth of penetration [ figure 2 ] .
the effects of sealer agitation techniques and type of sealer on depth and percentage of sealer penetration were analyzed , by performing nonparametric kruskal - wallis for overall analysis , and a series of mann - whitney u tests for pairwise comparison using statistical package of social sciences ( spss ) statistics 20 software .
confocal laser scanning microscopic photograph showing calculation of percentage of penetration of sealer in the dentinal tubules ( original magnification 10 ) confocal laser scanning microscopic photograph showing calculation of depth of penetration of sealer in the dentinal tubules ( original magnification 10 )
the percentage and depth of sealer penetration of different groups and intergroup comparison are summarized in tables 1 and 2 , respectively . shows mean and standard deviation of depth and percentage of sealer penetration of various groups at 3 and 6 mm levels intergroup comparison of depth and percentage of sealer penetration at 6 and 3 mm levels mean percentage and depth of sealer penetration of mta fillapex and ah plus sealer was greatest when ultrasonics was used for agitation and statistically significant ( p < 0.001 ) than lentulo spiral and counter - clockwise agitation techniques .
irrespective of method used for agitation , the percentage and depth of sealer penetration for mta fillapex was significantly greater ( p < 0.001 ) than ah plus .
the percentage and depth of sealer penetration for mta fillapex and ah plus were greater and highly significant ( p < 0.001 ) at 6 mm than 3 mm .
removal of smear layer and use of sealer to attain and impervious seal between the core material and root canal walls is considered an essential step of root canal treatment .
sealers which can penetrate into the dentinal tubules exert bactericidal effect by having a closer contact with the residual bacteria within the tubules .
in addition , sealer plugs inside the dentinal tubules provide a mechanical interlocking , thereby improving the retention of the filling material and reducing the microleakage along the root canal walls .
thus , both percentage and depth of sealer penetration might influence the outcome or success rate of endodontic therapy .
factors influencing sealer depth penetration in dentinal tubules are presence / absence of dentinal permeability ( the number and the diameter of tubules ) , root canal dimension , presence of water , and physical and chemical properties of the sealer .
the compound effect of physical properties viz flow , surface tension , solubility , viscosity , chemical composition , and working and setting time may influence penetration .
flow which is defined as the ability of a sealer to penetrate in irregularities , lateral canals , or dentinal tubules of the root canal system is one of the main physical factors to influence the tubular penetration .
as most endodontic sealers are pseudoplastic , their flow increases with increase of shear rate . on comparison with conventional sealers patel dv et al . , and gharib sr et al . , found better depth of penetration of resin - based sealer in dentinal tubules .
mta fillapex has excellent biocompatibility and bioactivity and displayed significantly higher ph up to 7 days period than ah plus .
studies based on the physical properties reported significantly greater flow of mta fillapex than ah plus .
therefore , this comparative study was conducted to evaluate and compare the quality of sealing of ah plus and mta fillapex .
clinically , rapid insertion or activation of a pseudoplastic sealer into the canal would decrease viscosity and increase the flow of sealer .
as very few studies have been conducted on the effect of sealer activation / placement and activation on sealing ability of root canal sealers therefore in the present study three activation techniques ( ultrasonics , lentulo spiral , and rotary counter - clockwise motion ) were chosen and the sealer distribution was analyzed .
amount of sealer , extent of activating instrument , and time for activation were standardized to minimize the errors .
all the analyzed activation techniques failed to show a consistent adaptation of both the sealers to the total circumference of the root canal walls .
however , mta fillapex showed significantly better ( p < 0.001 ) percentage and depth of sealer penetration than ah plus with all the techniques of sealer activation .
kuc , ia et al . , also reported greater mta fillapex sealer penetration than ah plus .
zhou h et al . , and silva ej et al . , found mta fillapex significantly more flowable than ah plus and attributed difference in composition and smaller particle size of the sealer for this property .
application of ultrasonics for activation led to significantly more ( p < 0.001 ) percentage and depth of both the sealers and is accordance to guimaraes bm et al . , the explanation for this is that the oscillating files in ultrasonics transmits the acoustic microstreaming energy and cause a greater depth of dentinal sealer penetration and coverage of root canal walls in the same manner as it promotes the penetration of irrigants in an area of anatomic complexities and the dentinal tubules . although activation of both the sealers with lentulo spiral resulted in more percentage and depth of penetration as compare to counter - clockwise rotation however , the difference was statistically insignificant ( p > 0.05 ) .
this is one of the pioneer studies evaluating effect of methods of activation on mta fillapex so it was difficult to compare the results obtained with previous studies .
lentulo spiral rotates and the spring portion pushes the sealer centrifugally while in counter - clockwise rotation with a file , the sealer tends to pool toward the tip of file but is not forced toward the walls .
irrespective of technique of activation and type of sealer , the depth , and percentage of penetration of sealer was significantly better at the 6 mm level than 3 mm level .
these findings are similar to other studies and could be because the number and diameter of dentinal tubules decreases on descending apically in the root canal and superior removal of smear layer .
in addition , the apical dentin is irregular in direction and density ; even some areas are devoid of dentinal tubules .
under the parameters of present study , it can be concluded that mta fillapex sealer exhibited better percentage and depth of penetration in the radicular dentinal tubules than ah plus .
ultrasonic activation of pseudoplastic sealers can significantly increase its percentage and depth of penetration and level of root canal can affect both , percentage , and depth of penetration of sealers in the dentinal tubules . | aim : to compare the effect of three root canal sealer activation techniques on percentage and depth of sealer penetration of mta fillapex and ah plus sealers.materials and methods : sixty teeth prepared till f5 protaper size were divided into three equal groups on the basis of sealer activation technique ( g1 : ultrasonics , g2 : lentulo spiral , and g3 : counter - clockwise rotary motion ) .
each group was further divided into two equal subgroups on the basis of type of sealer used : ah plus ( denstply , konstanz , germany ) or mta fillapex ( angelus , londrina , pr , brazil ) and obturated with gutta - percha .
horizontal sections at 3 and 6 mm from the apex were obtained and the percentage and depth of penetration of sealers into dentinal tubules were measured using confocal laser scanning microscopy ( clsm ) .
statistical analysis was performed utilizing kruskal - wallis and mann - whitney u tests with a significance level of 5%.results : g1 showed significantly ( p < 0.001 ) high percentage and depth of sealer penetration than g2 and g3 while the difference was insignificant ( p > 0.05 ) between g2 and g3.conclusion:percentage and depth of sealer penetration are influenced by the type of sealer used sealer activation technique and by the root canal level .
ultrasonic method of sealer activation and mta fillapex showed the best results . | [
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vision 2020 is a joint initiative by the world health organization ( who ) and the international agency for the prevention of blindness , that aims to eliminate avoidable blindness by the year 2020 .
the vision 2020 strategy depends on the development of district level plans for the prevention of avoidable blindness.[26 ] india was the first country in the world to initiate a public funded program for the prevention of blindness as a national priority health problem .
population - based surveys have been the main stay of information regarding the effective implementation and monitoring of such eye care programs .
are expensive and time consuming . rapid assessment of avoidable blindness ( raab ) survey is cheap and easy means of getting population - based data on prevalence and causes of blindness in people aged more than 50 years .
raab also has the other utility of monitoring programs at the unit / district level.[911 ] kolar district in south karnataka , india , has an estimated population of around 1.5 million , 51% of the population being males and 29% being over 50 years .
the aim of the study was to conduct a raab study in persons aged more than 50 years in kolar district in order to estimate the prevalence and causes of blindness .
this was also to help the ophthalmology and community medicine departments of the medical institution to develop student capacity as well as expose them to scientific survey methods of generating evidence for planning of eye care services .
the survey was carried out by a team consisting of trained personnel from the departments of ophthalmology and community medicine , sri devaraj urs medical college , kolar , karnataka , india .
the survey was carried out between march and june 2011 ( 4 months ) , in accordance with the helsinki declaration .
written informed consent was obtained from all study participants , after explaining the purpose of the study in their local language .
sample size was determined using a prevalence estimate of 4% for blindness ( who definition of presenting vision < 20/400 in better eye ) among those aged over 50 years .
the prevalence estimate was assumed to be around 4% considering the recent raab survey conducted across india which gave prevalence of blindness using the same definition to be around 3.6% . using 95% confidence interval , 22.5% precision , design effect of 1.5 and 10% nonresponse rate , sample size was calculated to be 3017 , which would require 61 clusters of 50 people aged over 50 years . using the population data from the last census ( 2001 ) and the growth rate for 9 years , the population was estimated for end of 2010 and used as a sampling frame .
a list of wards and villages in urban and rural areas was prepared taluk ( revenue division ) wise . in each , the population size of people aged over 50 years was listed .
households within each cluster were selected by compact segment sampling . a map of the selected cluster was drawn and divided into equal segments that would give
segments were numbered and one segment was chosen by draw of lots . to be eligible for inclusion an individual had to reside in that household for at least the previous 6 months . in each cluster ,
the people in the selected cluster were briefed about the survey 23 days in advance by the local health worker along with the public relations officer of the team .
if an eligible person was not available during the survey , at least two more attempts were made to assess information .
if after repeated visits , examination could not be done , information of his visual status was obtained from his relatives or neighbors .
standard raab protocol was used for gathering information and for eye examination . a survey form comprising seven sections
the form consisted of general information ; vision and pin hole examination ; lens status ; principal cause of visual impairment ; history if not examined ; and barriers to uptake of cataract surgery and details of cataract surgery if operated .
visual acuity ( va ) was measured using a tumbling snellen - e chart using optotype size 20/60 on one side and 20/200 on the other .
all measurements were taken in full daylight with available correction . if visual acuity was less than 20/60 in either eye , pin hole vision was tested .
if presenting vision was < 20/60 , then pupil was dilated and ophthalmoscopy done to assess the cause of blindness .
the interobserver agreement between the two teams was good as observed by the kappa value ( > 0.60 ) .
double data entry and analysis was done using the raab software program version 4.02 . to check for errors made during data entry of the survey record forms ,
the data are entered twice by different data entry clerks in two separate databases and then compared .
sample size was determined using a prevalence estimate of 4% for blindness ( who definition of presenting vision < 20/400 in better eye ) among those aged over 50 years .
the prevalence estimate was assumed to be around 4% considering the recent raab survey conducted across india which gave prevalence of blindness using the same definition to be around 3.6% . using 95% confidence interval , 22.5% precision , design effect of 1.5 and 10% nonresponse rate , sample size was calculated to be 3017 , which would require 61 clusters of 50 people aged over 50 years .
using the population data from the last census ( 2001 ) and the growth rate for 9 years , the population was estimated for end of 2010 and used as a sampling frame .
a list of wards and villages in urban and rural areas was prepared taluk ( revenue division ) wise . in each , the population size of people aged over 50 years was listed .
households within each cluster were selected by compact segment sampling . a map of the selected cluster was drawn and divided into equal segments that would give
segments were numbered and one segment was chosen by draw of lots . to be eligible for inclusion
an individual had to reside in that household for at least the previous 6 months . in each cluster
, the survey team visited each household accompanied by local health worker to facilitate compliance .
the people in the selected cluster were briefed about the survey 23 days in advance by the local health worker along with the public relations officer of the team .
if an eligible person was not available during the survey , at least two more attempts were made to assess information .
if after repeated visits , examination could not be done , information of his visual status was obtained from his relatives or neighbors .
standard raab protocol was used for gathering information and for eye examination . a survey form comprising seven sections
vision and pin hole examination ; lens status ; principal cause of visual impairment ; history if not examined ; and barriers to uptake of cataract surgery and details of cataract surgery if operated .
visual acuity ( va ) was measured using a tumbling snellen - e chart using optotype size 20/60 on one side and 20/200 on the other .
all measurements were taken in full daylight with available correction . if visual acuity was less than 20/60 in either eye , pin hole vision was tested .
if presenting vision was < 20/60 , then pupil was dilated and ophthalmoscopy done to assess the cause of blindness .
the interobserver agreement between the two teams was good as observed by the kappa value ( > 0.60 ) .
double data entry and analysis was done using the raab software program version 4.02 . to check for errors made during data entry of the survey record forms ,
the data are entered twice by different data entry clerks in two separate databases and then compared .
a total of 3050 persons aged over 50 years were included in the study and 2907 ( 95.3% ) of them were examined . of them
the sampled population was relatively representative of the district population in terms of age and sex distribution .
the overall unadjusted prevalence of blindness from all causes in persons aged over 50 years was 3.9% ( 95% ci 2.75.1 ) .
table 1 shows the data regarding prevalence of blindness ( va < 20/400 in better eye with available correction ) ; severe visual impairment ( va < 20/200 20/400 in better eye with available correction ) and moderate visual impairment in persons ( va < 20/60 20/200 in better eye with available correction ) .
the age and sex adjusted prevalence of blindness , severe visual impairment , and moderate visual impairment was 3.4% , 3.1% , and 9.7% , respectively .
sample prevalence of blindness , severe visual impairment and moderate visual impairment all causes untreated cataract was the primary cause of bilateral blindness ( 75% ) and severe visual impairment ( 73% ) .
refractive errors were the most common cause of moderate visual impairment ( 56% ) and second most common cause of severe visual impairment ( 11% ) .
avoidable causes accounted for 91% of all cases of blindness and 95% of cases of severe visual impairment [ table 2 ] .
causes of blindness ( va < 20/400 ) , severe visual impairment ( va 20/20020/400 ) and moderate visual impairment ( va 20/6020/200 ) the main barriers to uptake of cataract surgery were no one to accompany ( 27% ) ; waiting for maturity ( 27% ) ; do not know how to get surgery done ( 10% ) ; and old age no need ( 7% ) . the cataract surgical coverage ( csc ) in persons with va < 20/400 was high , with 82% of those requiring surgery having received the same .
for people with va < 20/200 and va < 20/60 , 72% and 64% , respectively of those needing surgery had received it [ table 3 ] . cataract surgical coverage by persons and eyes sex wise of the 707 eyes , which had received surgery , 641 ( 90.7% ) had an intra - ocular lens ( iol ) implantated .
among the patients with iol , 72.7% had va of 20/60 or more with available correction [ table 4 ]
. in patients operated less than 5 years back , 86% of patients with iol had best corrected va of more than or equal to 20/60 , when compared with 79% in patients with iol operated more than 5 years back . around 85% of patients were satisfied with the results of cataract surgery .
ocular comorbidities , operative complications and long - term complications were the principal reasons for poor outcome in eyes operated less than 3 years back .
postoperative visual acuity with available correction low vision ( persons with va < 20/60 in better eye with correction and not due to cataract , refractive error , or uncorrected aphakia ) was seen in 46 persons ( 1.6% ) .
in india , eye care planning and monitoring under the national program for control of blindness has been guided by population - based surveys .
rapid assessment techniques , which provide reliable estimates have been used for the past 16 years and have been the basis for district level programming .
the prevalence of blindness ( va < 20/400 ) was 3.9% in our study , which is almost similar to the raab study conducted across various states in india , which gave a prevalence of 3.6% .
the raab india study which covered gulbarga district in karnataka , gave a prevalence of 4.3% for that district .
the prevalence of blindness in our study is on the higher side when compared with other studies from kenya , bangladesh , china , palestinian territories and malawi where blindness prevalence ranged from 2.0% to 3.7% .
consequently , even though there has been a sharp increase in outreach programs and service delivery , this has been offset by the increasing elderly population as a result of increased life expectancy . in our study , almost 91% of blindness was avoidable .
untreated cataract still continues to be the major cause of blindness and severe visual impairment .
refractive errors and uncorrected aphakia are the other leading avoidable causes . despite the increased csc , there are an estimated 4700 people [ table 5 ] who are having bilateral cataract in kolar district , extrapolating the survey findings
. this cataract burden can only be reduced by proper taluk wise segmentation of the cataract blind and targeting the community outreach programs toward these areas . spectacle provision to the needy at a peripheral level by means of mobile refraction units and spectacle dispensing outfits
age and sex adjusted prevalence modified strategies in the form of extensive health awareness and health education campaigns through a decentralized approach involving all major health care providers at the grass root level , down to the remote rural level could be one of the positive steps in reducing this cataract burden .
waiting for maturity. this indirectly indicates that patients have been told to wait and sent back , which is an indicator of service delivery deficiency .
such people once turned back are unlikely to return back because of reasons such as lack of funds for conveyance to the hospital , loss of daily wages during the visit to the hospital , and relative lack of knowledge about when to return .
thus not only increasing the outreach programs but also concentrating on proper case selection , good surgical techniques , proper follow - up care and spectacle provision will definitely reduce the barriers and improve the outcome after cataract surgery .
this could be due to the fact that increased percentage of males seeks eye care services as reflected in the increased csc among males .
also females are less likely to report a need for sight than males.[1622 ] the strengths of our study was ready availability of taluk wise population data and the survey teams being trained by a certified raab trainer .
even though , there is a decline in prevalence of blindness , modified strategies need to be implemented to tackle the burden of untreated cataract .
raab done at regular intervals is an effective tool to quantify the problem of blindness and monitor the implementation of eye care programs . | background : more than 90% of visual impairment can either be treated or avoided .
rapid assessment of avoidable blindness methodology provides valid estimates in short time to assess magnitude and causes of blindness.aims:to estimate the prevalence and causes of blindness in persons above 50 years in kolar , south india , using the above methodology.materials and methods : sixty one clusters of 50 people aged above 50 years were selected by probability - proportionate to size sampling .
participants were evaluated using a standardized survey form .
persons with vision < 20/60 were dilated and examined by an ophthalmologist.results:of the 3050 people listed 2907 were examined ( 95.3% ) .
prevalence of bilateral blindness in persons was 3.9% ; severe visual impairment 3.5% , and visual impairment 10.4% .
untreated cataract was the leading cause of blindness ( 74.6% ) and severe visual impairment ( 73.3% ) .
avoidable causes of blindness accounted for 91.2% of all blindness and 95.0% of severe visual impairment .
waiting for maturity and no one to accompany were the most common barriers to uptake of cataract surgery.conclusion:untreated cataract continues to be the leading cause of avoidable blindness .
modified strategies need to be implemented to tackle the burden of cataract blindness . | [
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they are usually encountered as incidental findings in magnetic resonance imaging ( mri ) , or in arthroscopy .
they may originate from both the cruciate ligaments and the menisci , from the popliteus tendon and alar folds , infrapatellar fat pad of hoffa , and subchondral bone cysts .
those arising from the hoffa s fat pad , usually present as palpable mass at anterior aspect of the knee joint .
we report a case of intraarticular ganglion cyst of knee arising from the infrapatellar fat pad and protruding anterolaterally through retinacular rent into the subcutaneous plane .
a 19-year - old young man , presented with a painless gradually increasing swelling at the anterior aspect of left knee of 9 months duration .
mri scan revealed a multilobulated , cyst with septations within the anterior aspect of the knee joint , just inferolateral to the patella , with deep extension into the infrapatellar fat pad , and superficial extension into the subcutaneous space across the retinaculum .
after diagnostic arthroscopy , we performed an open excision of the cystic mass and confirmed the retinacular rent pre - operatively .
arthroscopic resection and debridement is the gold standard treatment in ganglion cyst of the knee .
however , a subcutaneous extension may lead to incomplete arthroscopic resection : leaving behind the residual tissue which may cause recurrence .
therefore , proper pre - operative evaluation of mr images of these cases is very important .
a ganglion is a cystic tumor - like lesion of unknown etiology , surrounded by a dense network of connective tissue , filled with a gelatinous fluid containing hyaluronic acid and other mucopolysaccharides .
intra - articular ganglion cysts of the knee joint are uncommon . they are usually encountered as incidental findings in magnetic resonance imaging ( mri ) , or in arthroscopic examination .
they may originate from both the cruciate ligaments and the menisci , from the popliteus tendon and alar folds , infrapatellar fat pad of hoffa , and subchondral bone cysts .
those arising from the hoffa s fat pad have been reported to present as palpable mass at anterior aspect of knee joint [ 2 - 5 ] ; however , to the best of our knowledge , none of them had subcutaneous communications across the retinaculum .
we report a case of intra - articular ganglion cyst of knee arising from the infrapatellar fat pad and protruding anterolaterally through retinacular rent into the subcutaneous plane .
a.a.m . , a 19-year - old young man , presented with a painless gradually increasing swelling at the anterior aspect of left knee for last 9 months .
there was no history of trauma , local injections , instability , locking episodes , clicking , snapping , or any constitutional symptoms .
clinical examination revealed a 2.5 cm x 2.5 cm round , soft , cystic , non - tender , irreducible swelling at anterolateral aspect of left knee 1.5 cm above the lateral joint line just lateral to the patellar tendon with discoloration of the overlying skin .
it was partially mobile , not fixed to the extensor mechanism or overlying skin , and was more prominent in knee extension ( fig .
1 ) . he could squat and sit cross - legged without any discomfort with a normal range of movement .
there was no effusion , no joint line tenderness , and no evidence of ligamentous laxity .
pre - operative clinical pictures showing the ganglion cyst at anterolateral aspect of left knee in various degrees of knee flexion .
mri scan revealed a multilobulated , cyst with septations within the anterior aspect of the knee joint , just inferolateral to the patella , with deep extension into the infrapatellar fat pad .
( a ) normal radiograph except increased soft tissue shadow , ( b ) parasagittal and axial mr images showing the ganglion cyst from infrapatellar fat pad extending subcutaneously across the retinaculum .
then we went for open excision of the cystic mass through lateral parapatellar approach ( incision included that of the anterolateral arthroscopic portal ) .
the cyst was found to be protruding just beneath the skin through a retinacular rent ( fig .
however , the entire mass was taken out , but we had to sacrifice the fat pad almost entirely .
post - operatively the patient underwent appropriate rehabilitation making an uneventful recovery and returned to his normal activities .
he was symptom - free in his last follow - up at 6 months post - operatively .
between the first description of an anterior cruciate ligament ( acl ) ganglion by caan in 1924 during a routine autopsy and the early 1990s , only a handful of sporadic cases were described in the literature .
the last 30 years have seen a huge increase in the number of these cases being reported owing to the widespread use of both mri and arthroscopy .
the prevalence of intra - articular cystic knee masses is 1.3% in mri and 0.6% in arthroscopy .
several theories have been suggested : ( a ) synovial tissue herniation , ( b ) mucinous degeneration of connective tissue after trauma , ( c ) synovial ectopia or displacement during embryogenesis , etc . .
the histological finding that ganglia are fluid - filled structures without any epithelial lining confirms that they are not true cysts , and thus favors the degenerative theory over others ; and , even though , ganglia may develop in the absence of trauma , it is postulated that repetitive microtrauma from joint and soft tissue motion may play an important role .
intra - articular ganglia of knee originates most commonly from the acl accounting for more than 50% cases ; whereas , the location at infrapatellar fat pad is far less common ( approximately 4% ) . however , only 10% of them are symptomatic with most being incidental finding on mri or arthroscopy .
the symptoms are usually non - specific , like knee pain , locking , clicking or popping sensation , decreased range of motion , etc . , and depend on the site and size of the cyst .
ganglia anterior to the acl tend to limit extension , whereas those posterior to the posterior cruciate ligament often limit knee flexion .
mri is the investigation of choice because it is the most sensitive , specific accurate , and noninvasive method for depicting such cystic masses , including their size and location , and to detect associated intra - articular pathologies . for intra - articular ganglion cyst in the infrapatellar fat pad
, fat - suppressed contrast - enhanced mri could be useful , because a thin , rim - enhancing feature of intra - articular ganglion cyst allows it to differentiate from synovial hemangioma and synovial sarcoma . among the various treatments available , arthroscopic resection and debridement are currently the preferred procedure ; open surgery may be necessary in particular cases only .
after diagnostic arthroscopy , we performed an open excision of the ganglion cyst since it was not clearly visible on arthroscopy ; moreover , we did not have any previous experience of arthroscopic resection of intra - articular ganglion cysts .
hence , in view of the high recurrence rate after incomplete removal of ganglion , we preferred open excision over arthroscopic resection . although recurrence is rare after arthroscopic or open surgical treatment of ganglion cyst of knee , the fact that it does occur in other areas even after excision , this patient should be followed up on regular basis .
current literature suggests arthroscopic resection and debridement as the gold standard treatment of ganglion cyst of the knee .
however , a subcutaneous extension may lead to incomplete arthroscopic resection : leaving behind the residual tissue which may cause recurrence .
therefore , proper pre - operative evaluation of mr images of these cases is very important .
they are usually encountered as incidental findings in mri , or in arthroscopy . arthroscopic resection and debridement
is regarded as the gold standard treatment in ganglion cyst of the knee . however , very rarely , these masses may extend subcutaneously across the retinaculum .
this may lead to incomplete arthroscopic resection : leaving behind the residual tissue which may cause recurrences .
therefore , proper pre - operative evaluation of mr images of these cases is very important . | introduction : intra - articular ganglion cysts of the knee joint are rare occurrences .
they are usually encountered as incidental findings in magnetic resonance imaging ( mri ) , or in arthroscopy .
they may originate from both the cruciate ligaments and the menisci , from the popliteus tendon and alar folds , infrapatellar fat pad of hoffa , and subchondral bone cysts .
those arising from the hoffa s fat pad , usually present as palpable mass at anterior aspect of the knee joint .
we report a case of intraarticular ganglion cyst of knee arising from the infrapatellar fat pad and protruding anterolaterally through retinacular rent into the subcutaneous plane.case report : a 19-year - old young man , presented with a painless gradually increasing swelling at the anterior aspect of left knee of 9 months duration .
mri scan revealed a multilobulated , cyst with septations within the anterior aspect of the knee joint , just inferolateral to the patella , with deep extension into the infrapatellar fat pad , and superficial extension into the subcutaneous space across the retinaculum .
after diagnostic arthroscopy , we performed an open excision of the cystic mass and confirmed the retinacular rent pre-operatively.conclusion:arthroscopic resection and debridement is the gold standard treatment in ganglion cyst of the knee .
however , a subcutaneous extension may lead to incomplete arthroscopic resection : leaving behind the residual tissue which may cause recurrence .
therefore , proper pre - operative evaluation of mr images of these cases is very important . | [
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"pancreatitis is a major well - known complication of endoscopic retrograde cholangiopancreatography(...TRUNCATED) | " backgroundthe aim was to study the role of rectal diclofenac in prevention of post - endoscopic re(...TRUNCATED) | [2,1688,110,151,66268,117,114,698,27363,113,63140,49762,29899,19787,4430,9673,47409,144,15740,143,11(...TRUNCATED) |
"a 75-year - old male farmer presented to a primary care skin cancer practice in west australia with(...TRUNCATED) | " a case of trichilemmoma in continuity with a pigmented basal cell carcinoma is presented with derm(...TRUNCATED) | [2,7248,5196,19835,110,144,6722,8647,1592,12047,117,114,2822,11982,113,9100,7268,21725,29066,1483,11(...TRUNCATED) |
"today , the treatment of choice is surgical excision of the tongue , but before 1900 , surgery was (...TRUNCATED) | " summary \n introduction : macroglossia is a condition which influences the size and shape of the (...TRUNCATED) | [2,109,1000,113,136,692,117,112,3449,1611,9406,1589,122,7530,13456,23191,23816,791,113,8909,497,5038(...TRUNCATED) |
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- Task: Summarization
- Model: google/bigbird-pegasus-large-pubmed
- Dataset: scientific_papers
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