Rheumatoid Arthritis: Goldring SR

Goldring SR. · No affiliation provided · Ann Rheum Dis. · Pubmed #19213745 No free full text.

This publication has no abstract.

Goldring SR, Gravallese EM. · No affiliation provided · Arthritis Rheum. · Pubmed #15248201 links to  free full text

This publication has no abstract.

Walsh NC, Crotti TN, Goldring SR, Gravallese EM. · Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA 02115, USA. · Immunol Rev. · Pubmed #16313352 No free full text.

Abstract: Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Goldring SR. · Beth Israel Deaconess Medical Center, Harvard Medical School, New England Baptist Bone and Joint Institute. Harvard Institutes of Medicine, Boston, MA, USA. · Calcif Tissue Int. · Pubmed #14565589 No free full text.

Abstract: Inflammatory disorders such as rheumatoid arthritis (RA), may have profound effects on skeletal homeostasis. In contrast to physiologic remodeling in which mechanical influences and/or systemic endocrine hormones initiate the remodeling process, in disorders such as RA the recruitment of macrophage lineage cells to sites of inflammation and the action of local osteoclastogenic cytokines associated with the inflammatory process initiate the remodeling process. In both physiologic and pathologic remodeling, osteoclasts appear to be the principal cell type responsible for the bone resorption. In addition, many of the same cytokines and mediators are involved in physiologic and pathologic bone remodeling. These observations have important implications with respect to the development of therapeutic strategies to prevent bone loss in inflammatory conditions.

Goldring SR. · Harvard Medical School, New England Baptist Bone and Joint Institute, Boston, MA, USA. · Rheumatology (Oxford). · Pubmed #12817090 links to  free full text

Abstract: Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFalpha), have been implicated in the dysregulation of bone and cartilage remodelling characteristic of rheumatoid arthritis (RA). With respect to bone remodelling, both of these cytokines have been shown to up-regulate the production of the receptor activator of nuclear factor-kappaB ligand, which acts to enhance osteoclastic bone resorption. TNFalpha stimulates differentiation of osteoclast progenitors into mature osteoclasts and IL-1 acts directly on osteoclasts to increase the bone-resorbing capacity of these cells. IL-1 and TNFalpha also adversely affect cartilage remodelling, although IL-1 is more potent on a molar basis. This cytokine not only increases production of factors that stimulate cartilage matrix degradation, but also inhibits the synthesis of type II collagen and proteoglycans. Enhanced understanding of the mechanisms underlying the processes of joint destruction will allow more selective and specific application of therapeutic agents that target these proinflammatory cytokines and, thus, more effective management of patients with RA and other inflammatory disorders.

Goldring SR. · Harvard Medical School, New England Baptist Bone and Joint Institute, Boston, Massachusetts 02215, USA. · J Rheumatol Suppl. · Pubmed #12236623 No free full text.

Abstract: Focal bone erosions occur at the joint margins and in subchondral bone of patients with rheumatoid arthritis (RA). These erosions progress throughout the course of disease and generally correlate with disease severity. Tissue sections from sites of bone erosion in the rheumatoid joint show multinucleated cells with phenotypic characteristics of osteoclasts, the cells responsible for resorbing bone during physiologic remodeling. Factors known to directly or indirectly induce osteoclast differentiation and activation are found in the rheumatoid synovium. These include receptor activator of NF-kappaB ligand (RANKL), which plays a critical role in osteoclast differentiation, as well as a variety of proinflammatory cytokines, including intereukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), which upregulate RANKL. IL-1 also augments osteoclast activation, and TNF-alpha induces differentiation of early osteoclast precursors. In animal models of RA, RANKL is expressed at sites of bone erosion. Moreover, in a serum transfer model of inflammatory arthritis, animals unable to produce osteoclasts did not show evidence of bone resorption despite the presence of intense inflammation. These observations suggest that osteoclasts mediate focal bone erosions in RA and that targeting of osteoclasts and osteoclast mediated bone resorption represents a rational approach to preventing or reducing focal bone loss in RA.

Goldring SR. · Beth Israel Deaconess Medical Center, Harvard Medical School, and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA. · Curr Opin Rheumatol. · Pubmed #12118176 No free full text.

Abstract: Focal marginal joint erosions represent the radiographic hallmark of rheumatoid arthritis (RA). These bone changes are characteristically localized to the joint margins, but in addition, regions of focal bone resorption can be detected in the subchondral bone adjacent to the bone marrow space into which the synovial inflammatory tissues have extended. Because progressive destruction of the periarticular bone contributes significantly to joint dysfunction and disability in patients with RA, there is considerable interest in developing a better understanding of the pathologic mechanisms involved in this process and in developing therapies that can arrest these events. Previous analysis of joint tissues from patients with RA have provided morphologic evidence that osteoclasts are the cell types that mediate the focal bone resorption associated with the rheumatoid synovial lesion. Additional recent data from animal models have helped to further implicate these cells in the pathogenesis of focal bone erosions. Furthermore, analysis of RA synovium and joint tissues from animal models of inflammatory arthritis, as well as cell and tissues culture studies, have helped to define the cytokines and inflammatory mediators that are involved in the recruitment and activation of bone resorbing cells associated with focal bone erosions. These findings provide a rational framework for developing targeted therapies that can specifically inhibit or slow the progressive focal bone destruction associated with the rheumatoid synovial lesion.

Goldring SR, Gravallese EM. · Harvard Institutes of Medicine, Room 241, 4 Blackfan Circle, Boston, MA 02115, USA. · Curr Rheumatol Rep. · Pubmed #12010607 No free full text.

Abstract: Histopathologic characterization of bone erosions from patients with rheumatoid arthritis (RA) and studies performed in animal models of inflammatory arthritis provide strong evidence that osteoclasts play an important role in focal marginal and subchondral bone loss in inflammatory arthritis. Much has been learned concerning the factors responsible for the induction and activation of osteoclasts associated with the bone erosions in RA. Therapies that target these osteoclast-inducing factors or other aspects of osteoclast-mediated bone resorption represent potential targets for blocking or at least attenuating bone destruction in RA. The demonstration of the role of the newly described osteoclastogenic factor receptor activator of nuclear factor kappaB ligand in RA synovial tissues and the successful prevention of bone erosions in animal models of arthritis with its inhibitor osteoprotegerin provide hope that specific therapies can be developed for preventing bone and joint destruction in RA, particularly in situations in which disease-modifying agents are ineffective in controlling disease activity.

Goldring SR, Gravallese EM. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Res. · Pubmed #11094416 links to  free full text

Abstract: Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.

Goldring SR. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA 02215, USA. · Ann Rheum Dis. · Pubmed #11053093 links to  free full text

This publication has no abstract.

Gravallese EM, Goldring SR. · Beth Israel Deaconess Medical Center and New England Baptist Bone and Joint Institute, Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #11037873 links to  free full text

This publication has no abstract.

Goldring SR, Gravallese EM. · Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. · Curr Opin Rheumatol. · Pubmed #10803748 No free full text.

Abstract: Patients with rheumatoid arthritis are at risk for the development of a generalized form of bone loss affecting the axial and appendicular skeleton. In addition, juxta-articular osteopenia and focal erosion of marginal and subchondral bone are commonly seen. The pathogenesis of focal bone erosions is an area of active investigation. Studies of tissue sections from sites of bone erosion in rheumatoid arthritis and in animal models of inflammatory arthritis have identified multinucleated cells with the phenotype of osteoclasts in bone resorption lacunae in these sites, suggesting that osteoclasts mediate a component of this pathologic bone loss. Numerous soluble and cell-membrane factors produced by rheumatoid synovial tissues are likely to play a role in the initiation and progression of bone erosions. In addition, recent studies suggest a role for T lymphocytes and their products in osteoclast-mediated bone loss. This paper reviews the cellular mechanisms and factors implicated in bone erosions in rheumatoid arthritis, and discusses the possible therapeutic strategies suggested by these findings.

Goldring SR. · Harvard Medical School, Beth Israel Deaconess Medical Center and New England Baptist Hospital, Boston, Mass 02215 USA. · JAMA. · Pubmed #10659880 No free full text.

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Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA. dwang@unmc · Arthritis Res Ther. · Pubmed #17233911 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37 degrees C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.

Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. · Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia. · Rheumatology (Oxford). · Pubmed #16490750 links to  free full text

Abstract: OBJECTIVES: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion. METHODS: Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion. RESULTS: Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression. CONCLUSIONS: The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.

Brown C, Gaspar J, Pettit A, Lee R, Gu X, Wang H, Manning C, Voland C, Goldring SR, Goldring MB, Libermann TA, Gravallese EM, Oettgen P. · Beth Israel Deaconess Medical Center, Department of Medicine, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA. · J Biol Chem. · Pubmed #14715662 links to  free full text

Abstract: Angiogenesis is a critical component of the inflammatory response associated with a number of conditions. Angiopoietin-1 (Ang-1) is an angiogenic growth factor that promotes the chemotaxis of endothelial cells and facilitates the maturation of new blood vessels. Ang-1 expression is up-regulated in response to tumor necrosis factor-alpha (TNF-alpha). To begin to elucidate the underlying molecular mechanisms by which Ang-1 gene expression is regulated during inflammation, we isolated 3.2 kb of the Ang-1 promoter that contain regulatory elements sufficient to mediate induction of the promoter in response to TNF-alpha, interleukin-1beta, and endotoxin. Surprisingly, sequence analysis of this promoter failed to reveal binding sites for transcription factors that are frequently associated with mediating inflammatory responses, such as NF-kappaB, STAT, NFAT, or C/EBP. However, putative binding sites for ETS and AP-1 transcription factor family members were identified. Interestingly, among a panel of ETS factors tested in a transient transfection assay, only the ETS factor ESE-1 was capable of transactivating the Ang-1 promoter. ESE-1 binds to specific ETS sites within the Ang-1 promoter that are functionally important for transactivation by ESE-1. ESE-1 and Ang-1 are induced in synovial fibroblasts in response to inflammatory cytokines, with ESE-1 induction slightly preceding that of Ang-1. Mutation of a high-affinity ESE-1 binding site leads to a marked reduction in Ang-1 transactivation by ESE-1, inducibility by inflammatory cytokines, and DNA binding to the ESE-1 protein. Transcriptional profiling of cells transiently transfected with an ESE-1 expression vector demonstrates that the endogenous Ang-1 gene is directly inducible by ESE-1. Finally, Ang-1 and ESE-1 exhibit a similar and strong expression pattern in the synovium of patients with rheumatoid arthritis. Our results support a novel paradigm for the ETS factor ESE-1 as a transcriptional mediator of angiogenesis in the setting of inflammation.

Grall F, Gu X, Tan L, Cho JY, Inan MS, Pettit AR, Thamrongsak U, Choy BK, Manning C, Akbarali Y, Zerbini L, Rudders S, Goldring SR, Gravallese EM, Oettgen P, Goldring MB, Libermann TA. · New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, and Beth Israel Deaconess Medical Center Genomics Center, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #12746898 links to  free full text

Abstract: OBJECTIVE: To investigate the expression of the novel Ets transcription factor ESE-1 in rheumatoid synovium and in cells derived from joint tissues, and to analyze the role of nuclear factor kappaB (NF-kappaB) as one of the central downstream targets in mediating the induction of ESE-1 by proinflammatory cytokines. METHODS: ESE-1 protein expression was analyzed by immunohistochemistry using antibodies in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). ESE-1 messenger RNA (mRNA) levels were analyzed by reverse transcriptase-polymerase chain reaction or Northern blotting in human chondrocytes, synovial fibroblasts, osteoblasts, and macrophages, before and after exposure to interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), or lipopolysaccharide (LPS) with or without prior infection with an adenovirus encoding the inhibitor of nuclear factor kappaB (IkappaB). The wild-type ESE-1 promoter and the ESE-1 promoter mutated in the NF-kappaB site were cloned into a luciferase reporter vector and analyzed in transient transfections. Electrophoretic mobility shift assays (EMSAs) and supershift assays with antibodies against members of the NF-kappaB family were conducted using the NF-kappaB site from the ESE-1 promoter as a probe. RESULTS: Immunohistochemical analysis showed specific expression of ESE-1 in cells of the synovial lining layer and in some mononuclear and endothelial cells in RA and OA synovial tissues. ESE-1 mRNA expression could be induced by IL-1beta and TNFalpha in cells such as synovial fibroblasts, chondrocytes, osteoblasts, and monocytes. Transient transfection experiments and EMSAs showed that induction of ESE-1 gene expression by IL-1beta requires activation of NF-kappaB and binding of p50 and p65 family members to the NF-kappaB site in the ESE-1 promoter. Overexpression of IkappaB using an adenoviral vector blocked IL-1beta-induced ESE-1 mRNA expression. Chromatin immunoprecipitation further confirmed that NF-kappaB binds to the ESE-1 promoter in vivo. CONCLUSION: ESE-1 is expressed in synovial tissues in RA and, to a variable extent, in OA, and is specifically induced in synovial fibroblasts, chondrocytes, osteoblasts, and monocyte/macrophages by IL-1beta, TNFalpha, or LPS. This induction relies on the translocation of the NF-kappaB family members p50 and p65 to the nucleus and transactivation of the ESE-1 promoter via a high-affinity NF-kappaB binding site. ESE-1 may play a role in mediating some effects of proinflammatory stimuli in cells at sites of inflammation.

Gravallese EM, Pettit AR, Lee R, Madore R, Manning C, Tsay A, Gaspar J, Goldring MB, Goldring SR, Oettgen P. · Beth Israel Deaconess Medical Center, Department of Medicine, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #12525377 links to  free full text

Abstract: OBJECTIVES: To examine the potential role of the angiogenic growth factor angiopoietin-1 (Ang-1) in inflammatory arthritis. METHODS: Eighteen synovial tissue samples were obtained from 17 patients with a clinical diagnosis of rheumatoid arthritis (RA) and compared with six synovial tissue samples from six patients with osteoarthritis (OA). Ang-1 expression in synovial tissues was determined by immunohistochemistry and in situ hybridisation. Ang-1 mRNA and protein expression were also examined by northern blot analysis and enzyme linked immunosorbent assay (ELISA) in cultured synovial fibroblasts and human umbilical vein endothelial cells (HUVECs) before and after treatment with tumour necrosis factor (TNF)alpha. RESULTS: Ang-1 protein expression was detected by immunohistochemistry in 16/18 RA synovial tissue samples. Ang-1 protein was frequently observed in the synovial lining layer and in cells within the sublining synovial tissue, in both perivascular areas and in areas remote from vessels. In contrast, Ang-1 was only weakly detected in these sites in OA samples. Ang-1 mRNA and protein were also expressed in cultured synovial fibroblasts derived from patients with RA. In addition, induction of Ang-1 mRNA and protein was observed by northern blot analysis and ELISA after stimulation of RA synovial fibroblasts, but not HUVECs, with the proinflammatory cytokine TNF alpha. CONCLUSIONS: Ang-1 mRNA and protein are expressed in the synovium of patients with RA, and are up regulated in synovial fibroblasts by TNF alpha. Ang-1 may therefore be an important regulator of angiogenesis in inflammatory arthritis.

Hou WS, Li W, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring SR, Brömme D. · Mount Sinai School of Medicine, New York, New York 10029, USA. · Arthritis Rheum. · Pubmed #11920402 links to  free full text

Abstract: OBJECTIVE: To determine and compare the expression of cathepsins K and S proteins in joints with rheumatoid arthritis (RA) and osteoarthritis (OA) and to determine the effect of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) on the expression of cathepsin K in fibroblast-like synoviocytes. METHOD: Expression and localization of cathepsins K and S were determined by immunohistochemistry in the synovium of 10 RA- and 8 OA-affected joints. Northern and Western blot analyses were performed to analyze cathepsin K and S expression in primary fibroblast-like synoviocyte cultures from RA and OA patients. The effect of IL-1 beta and TNF alpha on the expression and secretion of cathepsin K in primary cultures of synoviocytes was determined by real-time polymerase chain reaction and Western blot analysis. Staining of in situ activity was used to identify active cathepsin K enzyme in primary synovial fibroblast cultures. RESULTS: Cathepsin K and S protein expression was identified in the synovium from patients with RA and OA. Cathepsin K protein was localized in synovial fibroblasts, stromal multinucleated giant cells, and, to a lesser degree, in CD68+ macrophage-like synoviocytes. Of note is the expression of cathepsin K in synovial fibroblasts and mononuclear macrophage-like cells at sites of cartilage erosion in RA and in interdigitating cells of lymphocyte-rich areas. In contrast, cathepsin S expression was restricted to CD68+ macrophage-like synoviocytes, interdigitating cells, and endothelial cells of blood vessels. Cathepsin K protein expression in the interstitial areas and perivascular regions of RA-derived synovial specimens was 2-5 times higher than in OA samples (P < 0.001), whereas the expression of cathepsin S did not significantly differ in these diseases. Cathepsin K expression levels in normal synovium were low and restricted to fibroblast-like cells. Of note, cathepsin K also was expressed in repairing fibrocartilage in 1 OA specimen. Primary cell cultures of RA- and OA-derived synovial fibroblasts expressed comparable amounts of cathepsin K at the transcript and protein levels. Both cell cultures secreted mature cathepsin K as well as procathepsin K, and expressed active cathepsin K in cytosolic vesicles. In contrast, neither RA- nor OA-derived fibroblasts expressed detectable levels of cathepsin S. IL-1 beta and TNF alpha stimulated the transcript (7-8-fold) and protein expression (2-fold) of cathepsin K (P < 0.05) in primary synovial fibroblast cultures, without differences in expression between RA- and OA-derived synovial fibroblasts. CONCLUSION: The presence of cathepsin K polypeptide in synovial fibroblasts and macrophage-like cells in normal, OA, and RA synovia suggests a constitutive expression of this protease and a role in synovial remodeling. The comparable increase in cathepsin K expression after stimulation of RA- and OA-derived synovial fibroblasts with IL-1 beta and TNF alpha further suggests that the expression of cathepsin K is independent of cellular alterations leading to the invasive phenotype of RA-synovial fibroblasts. However, the overexpression of cathepsin K in RA synovia due to an increase in the number of cathepsin K-expressing cells identifies this enzyme as a candidate protease for the pathologic degradation of articular cartilage. Cathepsin S expression in macrophage-like synoviocytes suggests dual activity in antigen presentation and matrix degradation in the inflamed synovia.

Pettit AR, Ji H, von Stechow D, Müller R, Goldring SR, Choi Y, Benoist C, Gravallese EM. · Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA. · Am J Pathol. · Pubmed #11696430 links to  free full text

Abstract: There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.

Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR. · Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, and Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #10693863 links to  free full text

Abstract: OBJECTIVE: Osteoclast differentiation factor (ODF; also known as osteoprotegerin ligand, receptor activator of nuclear factor kappaB ligand, and tumor necrosis factor-related activation-induced cytokine) is a recently described cytokine known to be critical in inducing the differentiation of cells of the monocyte/macrophage lineage into osteoclasts. The role of osteoclasts in bone erosion in rheumatoid arthritis (RA) has been demonstrated, but the exact mechanisms involved in the formation and activation of osteoclasts in RA are not known. These studies address the potential role of ODF and the bone and marrow microenvironment in the pathogenesis of osteoclast-mediated bone erosion in RA. METHODS: Tissue sections from the bone-pannus interface at sites of bone erosion were examined for the presence of osteoclast precursors by the colocalization of messenger RNA (mRNA) for tartrate-resistant acid phosphatase (TRAP) and cathepsin K in mononuclear cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify mRNA for ODF in synovial tissues, adherent synovial fibroblasts, and activated T lymphocytes derived from patients with RA. RESULTS: Multinucleated cells expressing both TRAP and cathepsin K mRNA were identified in bone resorption lacunae in areas of pannus invasion into bone in RA patients. In addition, mononuclear cells expressing both TRAP and cathepsin K mRNA (preosteoclasts) were identified in bone marrow in and adjacent to areas of pannus invasion in RA erosions. ODF mRNA was detected by RT-PCR in whole synovial tissues from patients with RA but not in normal synovial tissues. In addition, ODF mRNA was detected in cultured adherent synovial fibroblasts and in activated T lymphocytes derived from RA synovial tissue, which were expanded by exposure to anti-CD3. CONCLUSION: TRAP-positive, cathepsin K-positive osteoclast precursor cells are identified in areas of pannus invasion into bone in RA. ODF is expressed by both synovial fibroblasts and by activated T lymphocytes derived from synovial tissues from patients with RA. These synovial cells may contribute directly to the expansion of osteoclast precursors and to the formation and activation of osteoclasts at sites of bone erosion in RA.