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Functional analysis of an arthritogenic synovial fibroblast.

ABSTRACT: Increasing attention has been directed towards identifying non-T-cell mechanisms as potential therapeutic targets in rheumatoid arthritis. Synovial fibroblast (SF) activation, a hallmark of rheumatoid arthritis, results in inappropriate production of chemokines and matrix components, which in turn lead to bone and cartilage destruction. We have demonstrated that SFs have an autonomous pathogenic role in the development of the disease, by showing that they have the capacity to migrate throughout the body and cause pathology specifically to the joints. In order to decipher the pathogenic mechanisms that govern SF activation and pathogenic potential, we used the two most prominent methods of differential gene expression analysis, differential display and DNA microarrays, in a search for deregulated cellular pathways in the arthritogenic SF. Functional clustering of differentially expressed genes, validated by dedicated in vitro functional assays, implicated a number of cellular pathways in SF activation. Among them, diminished adhesion to the extracellular matrix was shown to correlate with increased proliferation and migration to this matrix. Our findings support an aggressive role for the SF in the development of the disease and reinforce the perspective of a transformed-like character of the SF.

SUBMITTER: Aidinis V

PROVIDER: S-EPMC165045 | biostudies-literature | 2003

REPOSITORIES: biostudies-literature

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Functional analysis of an arthritogenic synovial fibroblast.

Aidinis Vassilis V Plows David D Haralambous Sylva S Armaka Maria M Papadopoulos Petros P Kanaki Maria Zambia MZ Koczan Dirk D Thiesen Hans Juergen HJ Kollias George G

Arthritis research & therapy 20030314 3

Increasing attention has been directed towards identifying non-T-cell mechanisms as potential therapeutic targets in rheumatoid arthritis. Synovial fibroblast (SF) activation, a hallmark of rheumatoid arthritis, results in inappropriate production of chemokines and matrix components, which in turn lead to bone and cartilage destruction. We have demonstrated that SFs have an autonomous pathogenic role in the development of the disease, by showing that they have the capacity to migrate throughout ...[more]

PMID: 12723986

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Project description:IntroductionActivated synovial fibroblasts are thought to play a major role in the destruction of cartilage in chronic, inflammatory rheumatoid arthritis (RA). However, profound insight into the pathogenic mechanisms and the impact of synovial fibroblasts in the initial early stages of cartilage destruction is limited. Hence, the present study sought to establish a standardised in vitro model for early cartilage destruction with native, intact cartilage in order to analyse the matrix-degrading capacity of synovial fibroblasts and their influence on cartilage metabolism.MethodsA standardised model was established by co-culturing bovine cartilage discs with early-passage human synovial fibroblasts for 14 days under continuous stimulation with TNF-alpha, IL-1beta or a combination of TNF-alpha/IL-1beta. To assess cartilage destruction, the co-cultures were analysed by histology, immunohistochemistry, electron microscopy and laser scanning microscopy. In addition, content and/or neosynthesis of the matrix molecules cartilage oligomeric matrix protein (COMP) and collagen II was quantified. Finally, gene and protein expression of matrix-degrading enzymes and pro-inflammatory cytokines were profiled in both synovial fibroblasts and cartilage.ResultsHistological and immunohistological analyses revealed that non-stimulated synovial fibroblasts are capable of demasking/degrading cartilage matrix components (proteoglycans, COMP, collagen) and stimulated synovial fibroblasts clearly augment chondrocyte-mediated, cytokine-induced cartilage destruction. Cytokine stimulation led to an upregulation of tissue-degrading enzymes (aggrecanases I/II, matrix-metalloproteinase (MMP) 1, MMP-3) and pro-inflammatory cytokines (IL-6 and IL-8) in both cartilage and synovial fibroblasts. In general, the activity of tissue-degrading enzymes was consistently higher in co-cultures with synovial fibroblasts than in cartilage monocultures. In addition, stimulated synovial fibroblasts suppressed the synthesis of collagen type II mRNA in cartilage.ConclusionsThe results demonstrate for the first time the capacity of synovial fibroblasts to degrade intact cartilage matrix by disturbing the homeostasis of cartilage via the production of catabolic enzymes/pro-inflammatory cytokines and suppression of anabolic matrix synthesis (i.e., collagen type II). This new in vitro model may closely reflect the complex process of early stage in vivo destruction in RA and help to elucidate the role of synovial fibroblasts and other synovial cells in this process, and the molecular mechanisms involved in cartilage degradation.

Dataset Information

Functional analysis of an arthritogenic synovial fibroblast.

Publications

Functional analysis of an arthritogenic synovial fibroblast.

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