bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Human Osteoprogenitor Chemotaxis, Proliferation, Differentiation, and Bone Formation by Osteoblast Stimulating Factor-1/Pleiotrophin: Osteoconductive Biomimetic Scaffolds for Tissue Engineering
Authors: Yang Xuebin , Tare Rahul S , Partridge Kris A , Roach Helmtrud I , Clarke Nicholas MP , Howdle Steven M , Shakesheff Kevin M , Oreffo Richard OC 
Published: April 2006

Abstract
The process of bone growth, regeneration, and remodeling is mediated, in part, by the immediate cell-matrix environment. Osteoblast stimulating factor-1 (OSF-1), more commonly known as pleiotrophin (PTN), is an extracellular matrix-associated protein, present in matrices, which act as targets for the deposition of new bone. However, the actions of PTN on human bone progenitor cells remain unknown. We examined the effects of PTN on primary human bone marrow stromal cells chemotaxis, differentiation, and colony formation (colony forming unit-fibroblastic) in vitro, and in particular, growth and differentiation on three-dimensional biodegradable porous scaffolds adsorbed with PTN in vivo. Primary human bone marrow cells were cultured on tissue culture plastic or poly(DL-lactic acid-co-glycolic acid) (PLGA; 75:25) porous scaffolds with or without addition of recombinant human PTN (1 pg-50 ng/ml) in basal and osteogenic conditions. Negligible cellular growth was observed on PLGA scaffold alone, generated using a super-critical fluid mixing method. PTN (50 μg/ml) was chemotactic to human osteoprogenitors and stimulated total colony formation, alkaline phosphatase-positive colony formation, and alkaline phosphatase-specific activity at concentrations as low as 10 pg/ml compared with control cultures. The effects were time-dependent. On three-dimensional scaffolds adsorbed with PTN, alkaline phosphatase activity, type I collagen formation, and synthesis of cbfa-1, osteocalcin, and PTN were observed by immunocytochemistry and PTN expression by in situ hybridization. PTN-adsorbed constructs showed morphologic evidence of new bone matrix and cartilage formation after subcutaneous implantation as well as within diffusion chambers implanted into athymic mice. In summary, PTN has the ability to promote adhesion, migration, expansion, and differentiation of human osteoprogenitor cells, and these results indicate the potential to develop protocols for de novo bone formation for skeletal repair that exploit cell-matrix interactions.
In Vitro Acoustic Waves Propagation in Human and Bovine Cancellous Bone
Authors: Cardoso Luis , Teboul Frédéric , Sedel Laurent , Oddou Christian , Meunier Alain 
Published: April 2006

Abstract
The acoustic behavior of cancellous bone with regard to its complex poroelastic nature has been investigated. The existence of two longitudinal modes of propagation is demonstrated in both bovine and human cancellous bone. Failure to take into account the presence of these two waves may result in inaccurate material characterization.
Introduction: Acoustic wave propagation is now a commonly used nondestructive method for cancellous bone characterization. However, wave propagation in this material may be affected by fluid-solid interactions inherent to its poroelastic nature, resulting in two different longitudinal waves. This phenomenon has been demonstrated in previous studies and is in agreement with Biot's theory. The purpose of this paper is to extend these findings to human trabecular bone and to thoroughly investigate these two waves.
Materials and Methods: Sixty human and 14 bovine cancellous bone cubic specimens were tested in vitro in three different directions using an immersion acoustic transmission method. Original procedures were developed to quantify both velocity and attenuation characteristics of each wave. In term of attenuation, a modified broadband ultrasound attenuation (BUA), describing the rate of change of the frequency-dependent attenuation, was defined for each wave (FDUA).
Results: Both waves were identified in most of the specimens. The fast wave velocities demonstrated a negative linear correlation with porosity (1500–2300 m/s, R2 = 0.44, p &lt; 10−3), whereas the slow wave velocities exhibited two different behaviors: (1) a first set of data clearly dependent on porosity showing a positive linear correlation (1150–1450 m/s, R2 = 0.26, p &lt; 10−3) and (2) a second group independent on porosity. The fast wave FDUA (20–140 dB/cmMHz) showed a parabolic behavior and reached a maximum for 75% porosity (second degree relationship R2 = 0.41, p &lt; 10−3), whereas a positive linear behavior was observed for the slow wave FDUA (15–40 dB/cmMHz; R2 = 0.15, p &lt; 10−2).
Conclusions: Existence of two wave propagation modes were demonstrated in human cancellous bone. Our data suggest that, in some cases, the amplitude of the slow wave is much larger than the amplitude of the fast wave. For this reason, care should be taken when using measurement systems that incorporate simple threshold detection because the fast wave could remain undetected. Moreover, failure to consider the presence of these two waves could result in an inaccurate quantification of cancellous bone physical properties.
Tartrate-Resistant Acid Phosphatase Knockout Mice
Authors: Hayman Alison R , Cox Timothy M 
Published: April 2006

Abstract
TRACP is a lysosomal enzyme found in diverse tissues, where it is expressed in dendritic cells as well as osteoclasts and macrophages. To investigate the function of TRACP in vivo, we have generated mice in which the gene-encoding TRACP has been selectively disrupted by targeted homologous recombination in murine embryonic stem cells. Homozygous TRACP “knockout” mice have progressive foreshortening and deformity of the long bones and axial skeleton suggesting a role for TRACP in endochondral ossification. There is increased mineralization reflecting a mild osteopetrosis caused by reduced osteoclast modeling activity. These knockout mice also display an impairment of macrophage function with abnormal immunomodulatory cytokine responses. Superoxide formation and nitrite production were enhanced in stimulated macrophages lacking TRACP as was the secretion of the proinflammatory cytokines TNF-α, interleukin (IL)-1β, and IL-12. TRACP knockout mice showed delayed clearance of the microbial pathogen Staphylococcus aureus after sublethal intraperitoneal inoculation. The macrophages lacking TRACP showed an increase in tartrate-sensitive lysosomal acid phosphatase activity (LAP). The TRACP knockout mice were bred with mice lacking LAP. Mice lacking both TRACP and LAP had even shorter bones than the TRACP single knockouts. Osteopontin, identical to the T-cell cytokine η-1, accumulated adjacent to actively resorbing osteoclasts suggesting that both phosphatases are important for processing this protein. We propose that TRACP may be an important regulator of osteopontin/η-1 activity common to both the immune system and skeleton.
Disease-Specific Expression of Tartrate-Resistant Acid Phosphatase Isoforms
Authors: Janckila Anthony J , Nakasato Yuri R , Neustadt David H , Yam Lung T 
Published: April 2006

Abstract
The association between elevated serum type 5 TRACP activity and metabolic bone diseases has been recognized for many years. However, serum type 5 TRACP exists as two related isoforms: 5a and 5b. Only isoform 5b is osteoclast-derived; the origin and significance of isoform 5a has hardly been explored. We have used simultaneous immunoassays for type-5 TRACP activity and total type-5 TRACP protein in conjunction with non-denaturing gel electrophoresis and column chromatography to investigate the nature and significance of TRACP isoforms 5a and 5b in end-stage renal disease (ESRD) and rheumatoid arthritis (RA). Our studies have shown that TRACP activity and protein are elevated in ∼50% of sera from ESRD patients, which is caused by osteoclastic isoform 5b. We have also shown that total TRACP protein, but not TRACP activity, is elevated in ∼30% of sera from RA patients, which is caused by non-osteoclastic isoform 5a. When macrophages or dendritic cells (DC) were cultured in vitro, abundant TRACP 5a was secreted into the culture medium, whereas TRACP 5b was retained intracellularly by both cell types. This implicates macrophages and DC as potential sources of elevated TRACP 5a in RA. Because TRACP isoform expression may be disease-specific, it is important to be able to distinguish TRACP 5a from 5b. There are four criteria by which to do so: (1) TRACP 5a bears sialic acid residues while TRACP 5b does not; (2) the pH optimum for TRACP 5a is 5.2 while that for TRACP 5b is 5.8; (3) the specific activity of TRACP 5a is significantly lower than that of TRACP 5b; and (4) TRACP 5a is as an uncleaved polypeptide, whereas TRACP 5b is a proteolytically nicked disulfide-linked “heterodimer.” The differences in biochemical properties and disease-specific expression of TRACP isoforms 5a and 5b suggest that they are regulated differently and perform separate functions in a tissue-specific manner.
Rapid Loss of Bone Mineral Density of the Femoral Neck After Cessation of Ice Hockey Training: A 6-Year Longitudinal Study in Males
Authors: Gustavsson Anna , Olsson Tommy , Nordström Peter 
Published: April 2006

AbstractThe aim of this study was to evaluate the effect of training and reduced training on BMD in young ice hockey players during 6 years of follow-up. We found BMD gains in the femoral neck in the ice hockey group compared with controls. However, these gains were lost with reduced activity after cessation of career.Introduction: It has been suggested that increasing bone mass by intense physical activity during childhood and adolescence may decrease the risk of osteoporosis later in life.Materials and Methods: In this longitudinal study, 43 ice hockey players (16.7 ± 0.6 years) and 25 control subjects (16.8 ± 0.3 years) were studied at baseline and after a mean period of 30 and 70 months. The groups did not differ in weight or height. Bone mineral density (BMD; g/cm2) was measured for total body, femoral neck, and spine using DXA. Volumetric BMD (vBMD; mg/cm3) of the femoral neck was estimated.Results: The ice hockey players were found to have gained significantly more femoral neck BMD than controls (0.07 versus 0.03 g/cm2, p = 0.04) and to have gained femoral neck vBMD, whereas the controls did not (16 versus 0 mg/cm3, p = 0.049) between baseline and the first follow-up. At the first follow-up, the ice hockey players were found to have significantly higher BMD at the femoral neck and total body versus controls (p &lt; 0.05). Between the first and second follow-ups, 21 ice hockey players stopped their active sports career. During this time period, these subjects lost significantly more femoral neck BMD (0.10 versus 0.02 g/cm2, p &lt; 0.001) and femoral neck vBMD (38 versus 4 mg/cm3, p &lt; 0.001) compared with the 22 ice hockey players who continued training. The former ice hockey players also lost significantly more neck vBMD (38 versus 14 mg/cm3, p = 0.009) compared with the controls during the same period. At the second follow-up, only the 22 ice hockey players who had continued their training were found to have significantly higher BMD at the femoral neck (p = 0.01), total body (p = 0.04), and spine (p = 0.02) compared with the controls. The former athletes were found to have intermediate BMD at all sites.Conclusion: In summary, we have demonstrated fast BMD loss at the femoral neck after decreased physical activity in young men. We conclude that ice hockey training during childhood and adolescence may not prevent the development of osteoporosis of the femoral neck later in life if the activity is not maintained.
Racial Differences in the Effect of Early Milk Consumption on Peak and Postmenopausal Bone Mineral Density
Authors: Opotowsky Alexander R , Bilezikian John P 
Published: April 2006

Abstract
Studies of the effect of milk consumption on bone density have focused on white women. The applicability to other races is unclear. This study of 4316 women found a racial difference in the effect of early milk consumption on bone. Further study is required to evaluate the etiology of this difference.
Introduction: Early milk consumption has been found to influence bone mineral density positively throughout life. Previous studies leading to this finding focused on white women; there are no data to support the view that black women also gain an equivalent benefit from early milk consumption.
Materials and Methods: Using data from the Third National Health and Nutrition Examination Survey (NHANES III), we analyzed the relationship between reported childhood and teenage milk consumption and current hip bone mineral density at four sites (femoral neck, trochanter, intertrochanter, and total hip) among postmenopausal and 20- to 39-year-old non-Hispanic white (NHW) and black (NHB) women. Potential confounding variables were accounted for in the analysis.
Results: Controlling for age and body mass index, teenage milk consumption was significantly associated with higher bone mineral density at all four sites among both postmenopausal and 20- to 39-year-old white women, but was not associated with bone mineral density at any site among black women. A similar pattern was observed for childhood milk intake. The interaction between race and teenage milk consumption significantly explained postmenopausal bone mineral density at all sites, whereas the interaction between race and teenage milk consumption was significant at two of the four sites among the 20- to 39-year-old women.
Conclusion: The results show racial differences in the effect of early milk consumption on peak and postmenopausal bone mineral density.
Insulin-like Growth Factor-1 Rescues the Mutated FGF Receptor 3 (G380R) Expressing ATDC5 Cells From Apoptosis Through Phosphatidylinositol 3-Kinase and MAPK
Authors: Koike Mio , Yamanaka Yoshitaka , Inoue Masaru , Tanaka Hiroyuki , Nishimura Riko , Seino Yoshiki 
Published: April 2006

Abstract
An activated mutation in the FGFR3 gene causes ACH. To examine the effects of IGF-1, which is an important mediator of GH, on apoptosis, we analyzed a chondrogenic cell line expressing the FGFR3 mutants. Our findings that IGF-1 prevented the apoptosis through P13K and MAPK pathways may explain how GH treatment improves the disturbed bone growth in ACH.
Introduction: Achondroplasia (ACH), which is caused by a point mutation of the fibroblast growth factor receptor 3 (FGFR3) gene in the transmembrane domain (G380R), is one of the most common genetic forms of dwarfism. Recently, using a chondrogenic cell line, ATDC5, we have showed that the constitutively active FGFR3 mutants induced an apoptosis of chondrocytes. We have also reported that growth hormone (GH) treatment increased the growth rate in achondroplasia in parallel with the increment of serum levels of insulin-like growth factor (IGF)-1, suggesting an important role of IGF-1 in skeletal development. In this study, to clarify the mechanism by which GH treatment improved the phenotype of ACH patients, we examined the possible effects of IGF-1 on an apoptosis induced by FGFR3 mutant in ATDC5.
Materials and Methods: Using adenovirus vector, wildtype or mutant FGFR3 (G380R) was introduced into ATDC5. Analysis of apoptosis was estimated by TUNEL assay. Expression levels of apoptosis-related genes and activation of signaling molecules were analyzed by immunoblot.
Results: MTT assay showed that the cell number was reduced in ATDC5 cells expressing the mutant FGFR3 (G380R; ATDC5-mtR3 cells), suggesting that ATDC5-mtR3 cells might fall into apoptosis. IGF-1, which is an important mediator of GH, restored cell proliferation and reduced apoptosis in ATDC5-mtR3 cells. IGF-1 also decreased the ratio of Bax/Bcl-2 in the cells. To investigate which signaling cascade is responsible for antiapoptotic effects of IGF-1, we examined the role of phosphatidylinositol 3-kinase (PI3K) and MAPK in ATDC5-mtR3 cells. Specific inhibitors of PI3K or MAPK blocked the antiapoptotic effects of IGF-1 in ATDC5-mtR3 cells.
Conclusions: Our findings, showing IGF-1 prevents the apoptosis induced by FGFR3 mutation through the PI3K pathway and MAPK pathway, explain the mechanisms by which GH treatment improves the disturbed bone growth in ACH.
Activation of p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase by BMP-2 and Their Implication in the Stimulation of Osteoblastic Cell Differentiation
Authors: Guicheux J , Lemonnier J , Ghayor C , Suzuki A , Palmer G , Caverzasio J 
Published: April 2006

Abstract
Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression.
Introduction: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-β signaling.
Materials and Methods: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors.
Results: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level.
Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.
How Well Are Bones Designed to Resist Fracture?
Authors: Currey John D 
Published: April 2006

Abstract
Because bone is obviously in some way adapted to the loads falling on it and because fracture is usually the failure of mechanical competence of main clinical importance, it is often thought that bones are adapted to resist fracture. In this perspective, I consider that this may not be the case. Bones may be designed to be very stiff, and therefore highly mineralized, and therefore brittle; they may be adapted to normal loads, but not to the characteristic loads occurring in falls, or may be very poorly designed to stop cracks traveling once they have started. Bones may also potentially fail in completely contrasting modes, and therefore their design has to be a compromise that does not resist either mode completely successfully. The greatly differing fracture incidences in different bones seen in pre-senile adults suggest that safety factors have been adapted, over evolutionary time, to produce the best compromise for a host of different design constraints.
Bone Mass, Size, and Density in Children and Adolescents With Osteogenesis Imperfecta: Effect of Intravenous Pamidronate Therapy
Authors: Rauch Frank , Plotkin Horacio , Zeitlin Leonid , Glorieux Francis H 
Published: April 2006

Abstract
Cyclical intravenous therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study, we evaluated the effect of this therapy on lumbar spine bone mass (bone mineral content [BMC]), size (bone volume [BV]), and density (volumetric bone mineral density [vBMD]). Results from 56 patients (age, 0.2–15.9 years; 25 girls) on long-term pamidronate treatment were compared with those of 167 patients who had not received pamidronate before densitometry. In all patients who received pamidronate, BMC, BV, and vBMD increased above levels expected for untreated patients (p &lt; 0.001 in each case). After 4 years of treatment, BMC, BV, and vBMD were 154%, 44%, and 65% higher, respectively, in treated than in untreated patients who were matched for age and OI type. A multiple regression model showed that baseline BMC was negatively associated with the increase in BMC. In conclusion, the bone mass increase in pediatric OI patients receiving pamidronate is caused by increases in both bone size and density. Patients with larger deficits in bone mass at baseline have a more marked bone mass gain during therapy.
Leupaxin Is a Critical Adaptor Protein in the Adhesion Zone of the Osteoclast
Authors: Gupta Anandarup , Lee Beth S , Khadeer Mohammed A , Tang Zhihui , Chellaiah Meenakshi , Abu-Amer Yousef , Goldknopf Joshua , Hruska Keith A 
Published: April 2006

Abstract
Leupaxin is a cytoskeleton adaptor protein that was first identified in human macrophages and was found to share homology with the focal adhesion protein, paxillin. Leupaxin possesses several protein-binding domains that have been implicated in targeting proteins such as focal adhesion kinase (pp125FAK) to focal adhesions. Leupaxin can be detected in monocytes and osteoclasts, both cells of hematopoietic origin. We have identified leupaxin to be a component of the osteoclast podosomal signaling complex. We have found that leupaxin in murine osteoclasts is associated with both PYK2 and pp125FAK in the osteoclast. Treatment of osteoclasts with TNF-α and soluble osteopontin were found to stimulate tyrosine phosphorylation of both leupaxin and leupaxin-associated PYK2. Leupaxin was found to co-immunoprecipitate with the protein tyrosine phosphatase PTP-PEST. The cellular distribution of leupaxin, PYK2, and protein tyrosine phosphorylation-PEST co-localized at or near the osteoclast podosomal complex. Leupaxin was also found to associate with the ARF-GTPase-activating protein, paxillin kinase linker p95PKL, thereby providing a link to regulators of cytoskeletal dynamics in the osteoclast. Overexpression of leupaxin by transduction into osteoclasts evoked numerous cytoplasmic projections at the leading edge of the cell, resembling a motile phenotype. Finally, in vitro inhibition of leupaxin expression in the osteoclast led to a decrease in resorptive capacity. Our data suggest that leupaxin may be a critical nucleating component of the osteoclast podosomal signaling complex.