bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of cartilage growth: Modulation of balance between proteoglycan and collagen in vitro using chondroitinase ABC
Authors: Asanbaeva Anna , Masuda Koichi , Thonar Eugene J.‐M. A. , Klisch Stephen M. , Sah Robert L. 
Published: December 2006

AbstractObjectiveTo examine the cartilage growth–associated effects of a disruption in the balance between the swelling pressure of glycosaminoglycans (GAGs) and the restraining function of the collagen network, by diminishing GAG content prior to culture using enzymatic treatment with chondroitinase ABC.MethodsImmature bovine articular cartilage explants from the superficial and middle layers were analyzed immediately or after incubation in serum‐supplemented medium for 13 days. Other explants were treated with chondroitinase ABC to deplete tissue GAG and also either analyzed immediately or after incubation in serum‐supplemented medium for 13 days. Treatment‐ and incubation‐associated variations in tissue volume, contents of proteoglycan and collagen network components, and tensile mechanical properties were assessed.ResultsIncubation in serum‐supplemented medium resulted in expansive growth with a marked increase in tissue volume that was associated with a diminution of tensile integrity. In contrast, chondroitinase ABC treatment on day 0 led to a marked reduction of GAG content and enhancement of tensile integrity, and subsequent incubation led to maturational growth with minimal changes in tissue volume and maintenance of tensile integrity at the enhanced levels.ConclusionThe data demonstrate that a manipulation of GAG content in articular cartilage explants can distinctly alter the growth phenotype of cartilage. This may have practical utility for tissue engineering and cartilage repair. For example, the expansive growth phenotype may be useful to fill cartilage defects, while the maturational growth phenotype may be useful to induce matrix stabilization after filling defect spaces.
Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9
Authors: Cucchiarini Magali , Thurn Tanja , Weimer Anja , Kohn Dieter , Terwilliger Ernest F. , Madry Henning 
Published: December 2006

AbstractObjectiveHuman osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV‐mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage.MethodsWe monitored the synthesis and content of proteoglycans and type II collagen in 3‐dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno‐associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems.ResultsFollowing SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose‐dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage.ConclusionThese data support the concept of using direct, rAAV‐mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.
Isolation and chondroinduction of a dermis‐isolated, aggrecan‐sensitive subpopulation with high chondrogenic potential
Authors: Deng Ying , Hu Jerry C. , Athanasiou Kyriacos A. 
Published: December 2006

AbstractObjectiveTo develop a process that yields tissue‐engineered articular cartilage constructs from skin‐derived cells.MethodsDermis‐isolated, aggrecan‐sensitive (DIAS) cells were isolated using a modified rapid adherence process. The chondrogenic potential was measured by quantitative reverse transcriptase–polymerase chain reaction, enzyme‐linked immunosorbent assay, and immunohistochemistry. Filamentous actin (F‐actin) and vinculin organization was detected using fluorescence microscopy.ResultsThe rapid adherence process led to a selection of DIAS cells, <10% of the entire population. DIAS cells displayed greater chondroinduction potential, as evidenced by the formation of large numbers of chondrocytic nodules on aggrecan‐coated surfaces. In addition, these cells showed higher gene expression and protein production in terms of chondrocytic markers when compared with unpurified dermis cells. Similar patterns of F‐actin and vinculin organization were observed between DIAS cells and chondrocytes. Three‐dimensional constructs from chondroinduced DIAS cells produced greater amounts of cartilage matrix than constructs from the rest of the dermis populations.ConclusionThese findings show a series of steps that work together to form tissue‐engineered articular cartilage constructs using DIAS cells. Since skin presents a minimally invasive, relatively abundant cell source for tissue engineering, this study offers evidence of an efficient and stable technique to form cartilage constructs for future cartilage regeneration with autologous cells from skin.
Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee
Authors: Valdes Ana M. , Loughlin John , Oene Mark Van , Chapman Kay , Surdulescu Gabriela L. , Doherty Michael , Spector Tim D. 
Published: December 2006

AbstractObjectiveTo assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed‐sex, case–control study of clinical knee OA.MethodsGenetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50–86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.ResultsThe same FRZB 2‐marker single‐nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta‐analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).ConclusionOur results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.
Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis
Authors: Izmailova Elena S. , Paz Nancy , Alencar Herlen , Chun Miyoung , Schopf Lisa , Hepperle Michael , Lane Joan H. , Harriman Geraldine , Xu Yajun , Ocain Timothy , Weissleder Ralph , Mahmood Umar , Healy Aileen M. , Jaffee Bruce 
Published: December 2006

AbstractObjectiveThe NF‐κB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF‐κB activity is regulated by the IKK‐2 kinase during inflammatory responses. To elucidate how IKK‐2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody‐induced arthritis.MethodsML120B, a potent, small molecule inhibitor of IKK‐2, was administered to arthritic animals, and disease activity was monitored. NF‐κB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase–polymerase chain reaction was used to evaluate gene expression in joints. Protease‐activated near‐infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.ResultsOral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF‐κB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF‐κB pathway, i.e., KC, epithelial neutrophil–activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor α, interleukin‐1β, interleukin‐6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.ConclusionOur data demonstrate that IKK‐2 inhibition in the murine model of antibody‐induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis
Authors: Michel Joshua J. , Turesson Carl , Lemster Bonnie , Atkins Sarah R. , Iclozan Cristina , Bongartz Tim , Wasko Mary Chester , Matteson Eric L. , Vallejo Abbe N. 
Published: December 2006

AbstractObjectiveT cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28‐null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.MethodsSeventy‐two patients with RA (ages 35–84 years) and 53 healthy persons (32 young controls ages 19–34 years, 21 older controls ages 39–86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long‐term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA‐associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.ResultsChronic stimulation of CD28+ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56+,CD28‐null T cells than in patients with disease confined to the joints or in healthy controls. CD56+,CD28‐null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56+ T cells had skewed T cell receptor (TCR) α/β‐chain usage and restricted TCR third complementarity‐determining region spectra. Histologic studies showed that CD56+ T cells were components of cellular infiltrates in RA‐associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.ConclusionChronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR‐independent and TCR‐dependent activation pathways. We propose that accumulation of CD56+ T cells in RA contributes to maladaptive immune responses and that CD56+ T cells are potential targets for therapy.
Interleukin‐17 as a molecular target in immune‐mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin‐4
Authors: Sarkar Sujata , Tesmer Laura A. , Hindnavis Vindhya , Endres Judith L. , Fox David A. 
Published: December 2006

AbstractObjectiveOur previous studies have shown that murine dendritic cells (DCs) genetically modified to express interleukin‐4 (IL‐4) reduce the incidence and severity of murine collagen‐induced arthritis. The present studies were performed to assess the immunoregulatory mechanisms underlying this response, by assessing the effects of IL‐4 DCs on cytokine production by subsets of T helper cells.MethodsMale DBA mice ages 6–8 weeks old were immunized with type II collagen. Splenic T cells obtained during the initiation phase and the end stage of arthritis were cultured with IL‐4 DCs or untransduced DCs in the presence of collagen rechallenge. Interferon‐γ (IFNγ) and IL‐17 responses were measured. Antibodies to IL‐4, IL‐12, and IL‐23, and recombinant IL‐4, IL‐12, and IL‐23 were used to further study the regulation of T cell cytokine production by IL‐4 DCs.ResultsSplenic T cells obtained during the initiation phase of arthritis produced less IL‐17 when cultured in the presence of IL‐4 DCs, despite their production of increased quantities of other proinflammatory cytokines (IFNγ and tumor necrosis factor). T cell IL‐17 production after collagen rechallenge was not inhibited by a lack of IL‐23, since IL‐4–mediated suppression of IL‐17 was not reconstituted by IL‐23, an otherwise potent inducer of IL‐17 production by T cells. Although IL‐4 DCs can produce increased quantities of IL‐12 and IFNγ, suppression of IL‐17 production by IL‐4 DCs was independent of both. While IL‐17 production by T cells obtained during the initiation phase of arthritis was regulated by IL‐4 DCs, IL‐17 production by T cells obtained during end‐stage arthritis was not altered.ConclusionOur data suggest that IL‐4 DCs exert a therapeutic effect on collagen‐induced arthritis by targeting IL‐17. IL‐17 suppression by IL‐4 DCs is robust and is not reversed by IL‐23. Timing might be important in IL‐17–targeted therapy, since IL‐17 production by T cells obtained during end‐stage arthritis did not respond to suppression by IL‐4 DCs.
Evaluation of protease‐activated receptor 2 in murine models of arthritis
Authors: Busso Nathalie , Frasnelli Matthias , Feifel Roland , Cenni Bruno , Steinhoff Martin , Hamilton Justin , So Alexander 
Published: December 2006

AbstractObjectiveProtease‐activated receptor 2 (PAR‐2) activation has been linked to pro‐ and antiinflammatory cellular responses. We undertook this study to explore the importance of PAR‐2 activation in 4 murine models of arthritis and to analyze the expression of PAR‐2 in human arthritic synovium.MethodsZymosan‐induced arthritis (ZIA), K/BxN serum–induced arthritis, and Freund's complete adjuvant (CFA)–induced arthritis were generated in naive PAR‐2−/− mice and PAR‐2+/+ littermates. Antigen‐induced arthritis (AIA) was generated in immunized mice using methylated bovine serum albumin (mBSA). The severity of arthritis was assessed by clinical scoring, technetium uptake measurement, and histologic analysis. Immune responses to mBSA were also evaluated from AIA. The expression of PAR‐2 in synovial tissues from rheumatoid arthritis (RA) and osteoarthritis (OA) patients was compared.ResultsIn AIA, arthritis was significantly decreased in PAR‐2–deficient mice and was associated with decreased levels of anti‐mBSA IgG antibodies and lymph node cell proliferation. No difference in arthritis severity was seen in mice with ZIA, K/BxN serum–induced arthritis, and CFA‐induced arthritis. Synovial biopsy specimens from RA patients demonstrated significantly increased expression of PAR‐2 compared with those from OA patients.ConclusionPAR‐2 deficiency was found to modulate articular inflammation in murine models of arthritis that require prior immunization and was associated with reduced levels of anti‐mBSA IgG and lymph node cell proliferation in AIA. Expression of PAR‐2 in RA synovium was significantly higher than that in OA synovium, and this suggests that PAR‐2 is implicated in the pathogenesis of immune‐mediated forms of arthritis.
Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis
Authors: Hayer Silvia , Redlich Kurt , Korb Adelheid , Hermann Sonja , Smolen Josef , Schett Georg 
Published: December 2006

AbstractObjectiveTo determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.MethodsHuman tumor necrosis factor (TNF)–transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.ResultsInitial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus‐like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up‐regulation of interleukin‐1 (IL‐1) and IL‐6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.ConclusionStructural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.
Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen‐induced arthritis
Authors: Elsaid Khaled A. , Jay Gregory D. , Chichester Clinton O. 
Published: December 2006

AbstractObjectiveTo investigate the effect of arthritis development and progression on the integrity and function of lubricin and the relationship of lubricin to cartilage damage in a rat antigen‐induced arthritis model.MethodsArthritis was induced in the right knee joints, using methylated bovine serum albumin and Freund's complete adjuvant. Whole joint friction measurements were performed ex vivo with a modified Stanton pendulum configuration, and coefficients of friction (μ) were determined. Levels of messenger RNA (mRNA) for lubricin, cathepsin B, and interleukin‐1β (IL‐1β) in synovial tissue from control and affected joints were determined by quantitative polymerase chain reaction. Lubricin staining in cartilage was performed using a lubricin‐specific monoclonal antibody.ResultsThe μ values in excised right joints following arthritis induction were significantly (P < 0.001) higher than those in excised left joints. Lubricin mRNA expression levels in synovial tissue on days 4 and 7 after arthritis induction were significantly (P < 0.001) lower in the right joints compared with the left joints, whereas levels of cathepsin B and IL‐1β mRNA expression on days 4, 7, and 14 were significantly (P < 0.001) higher in the right joints than the left joints. Lubricin staining was diminished in cartilage from the right joints compared with the left joints.ConclusionElevated coefficients of friction in arthritic joints occur concurrently with enhanced proteolytic degradation by up‐regulated cathepsin B and other proteases, as well as decreased lubricin synthesis by synovial fibroblasts and superficial zone chondrocytes. Loss of joint lubrication is an early event in inflammatory arthropathy. Restoring chondroprotection and preventing potential wear‐induced cartilage degradation may require lubricin supplementation in synovial fluid.
Natural killer T cells in families of patients with systemic lupus erythematosus: Their possible role in regulation of IGG production
Authors: Green Matthew R. J. , Kennell Amy S. M. , Larche Maggie J. , Seifert Martin H. , Isenberg David A. , Salaman Myer R. 
Published: December 2006

AbstractObjectiveTo determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives.MethodsBlood samples were obtained from patients with SLE, their first‐degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56+ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double‐stranded DNA (dsDNA) were determined.ResultsThe frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti‐dsDNA in patients were associated with low frequencies of NKT cells.ConclusionThese results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.