The progressive destruction of cartilage and bone is one of the most characteristic features of rheumatoid arthritis (RA). It results form the concerted action of different cells types such as T cells, fibroblasts and macrophages that through direct contact as well as the release of cytokines form a cellular network in the inflamed synovium. Research of the last decade has provided evidence that RA synovial fibroblasts (RA-SF) contribute significantly to disease and play a major role in both initiating and driving the destructive process. It has been understood that intrinsic cellular activation, alterations in apoptosis and the attachment to cartilage and bone are critical prerequisites for the degradation of extracellular matrix.
The degradation of articular cartilage by activated RA-SF has been investigated in different in vitro and animal models. Among the latter, the SCID mouse model of RA has been used intensively to clarify the specific role of synovial fibroblasts in rheumatoid cartilage destruction. In this model, RA-SF are co-implanted with normal articular cartilage into severe combined immunodeficient (SCID) mice. As these mice do not reject the implants, the model allows studying the degradation of articular cartilage by RA-SF in the absence of human inflammatory cells. From the SCID mouse model it has been learnt that RA-SF maintain their activated phenotype in the absence of continuous inflammatory stimulation and progressively degrade cartilaginous matrix. As demonstrated by gene transfer experiments, modulation of intracellular signalling pathways such as the Ras-Raf-MAPK pathway, the NF-kappa B transcription factor and the p53 tumour suppressor gene alter the aggressive behaviour of RA-SF in the SCID mouse model of RA.
However, research has also demonstrated clearly that proinflammatory cytokines as produced by various cells in the rheumatoid synovium further enhance the aggressive potential of RA-SF. Apart form TNF alpha, IL–1, and IL-1 dependent pathways appear to play a central role.
It is now well established that RA-SF destroy the articular cartilage directly through the release of matrix degrading enzyme such as matrix metalloproteinases (MMPs), cathepsins and serine proteases. While several of these enzymes have been identified in the rheumatoid synovium and demonstrated to contribute to cartilage degradation, the specific role of individual members of these families is still poorly understood. In addition, despite a clear understanding of general mechanisms that regulate the expression of MMPs and cathepsins, specific pathways by which these enzymes are upregulated differentially in the course of disease need clarification. Current efforts focus on the modulation of enzymes that apart from degrading extracellular matrix directly, play a major role in activating other matrix degrading enzymes. Membrane-type MMPs (MT-MMPs) as well as the Plasmin system appear promising candidates for such approaches.
So far, fibroblasts have been associated with bone resorption mainly by indirect mechanisms such as the release of factors that enhance osteoclast activity and facilitate the differentiation of macrophages into osteoclast-like cells. Thus, fibroblasts of the rheumatoid synovium constitute a major source of the osteoclast differentiating factor (ODF) that appears to play a central role in the differentiation and activation of osteoclasts. However, recent data indicate that specific populations of activated fibroblasts such as from the synovial like interface membrane around loose joint prostheses are also capable of resorbing bone in vivo without the help of osteoclasts. Upon stimulation, such fibroblasts release large amounts of acidic components that may account for their ability to decalcify bone prior to its degradation. Using RT-PCR, in situ hybridization and immuno- transmission electron microscopy, we have been able to demonstrate that these cells express a vacuolar type ATPase (v-ATPase) on their cell surface that has been implicated in the H+ secretion by different cell types. It is concluded that subtypes of activated fibroblasts may not only enhance but also actively contribute to the bone resorption. The question of whether this applies also to RA-SF or is associated with different ways of cellular activation needs to be determined.
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