We used antigen-induced arthritis (AIA), which is induced by intraarticular injection of an antigen into the knee joint cavity of animals preimmunized with the same antigen. Thus, our study aimed at answering some fundamental questions of the biology of FLSs for the pathogenesis of arthritis. If an acute (short-term) arthritis were sufficient to induce persistent changes in FLS behavior, it could be hypothesized that these cells are rather accomplices than villains in the induction and perpetuation of chronic arthritis. This has not yet been proven experimentally, and we therefore aimed to elucidate if chronic inflammation is mandatory for arthritogenic transformation of FLSs in our mouse model. It is unknown whether this behavior can also be imprinted to non-immortalized FLSs isolated from arthritic wild-type mice.īased on the above-mentioned studies using FLSs from patients with RA, it is widely assumed that the arthritis-promoting effect of these cells is the consequence of long-standing chronic inflammation. So far, there is only one published study using cloned immortalized FLSs confirming the observation of an arthritogenic behavior of FLSs in a tumor necrosis factor (TNF)-transgenic mouse model. Thus, animal models are clearly needed for a better understanding of the contribution of fibroblasts to chronic inflammation and joint destruction in arthritis. Since the immunological process which finally triggers RA can precede the clinical disease onset by many years, the cascade of events eventually leading to FLS activation and disease cannot be reconstructed from patient material. Thus, although this model does not reflect all aspects of the complex pathogenesis of RA, it fosters the view that a permanent and autonomous activation of FLSs is central to disease progression. Furthermore, destructive fibroblasts migrate to and destroy unaffected cartilage co-transplanted in other anatomical locations upon transfer in immunodeficient mice. In such chimeric models, FLSs attach to and invade the co-implanted cartilage, and they recruit inflammatory cells. Since synovial membranes of RA patients contain a mixture of different cell types, in later studies FLSs were isolated prior to transfer into SCID mice. Early models used transplantation of whole RA synovial tissue to study the inflammatory and destructive features of synovial cells in an in vivo environment. A remarkable feature of FLSs is their ability to maintain their activated phenotype in tissue culture or upon engraftment in severe combined immunodeficient (SCID) mice. FLSs also produce matrix-degrading enzymes such as matrix metalloproteases (MMPs) and cathepsins and are thereby directly involved in joint destruction. Via their production of different inflammatory cytokines and chemokines, they can recruit inflammatory cells and sustain their persistence in inflamed joints. Fibroblast-like synoviocytes (FLSs) are the dominant cell type in the hyperplastic synovial membrane and are thought to play a key role in the pathogenesis of RA. Key histological features of RA are infiltration by cells from the innate and the adaptive immune system, hyperplasia of the synovial membrane, and destruction of cartilage and adjacent bone. Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the joints. This challenges current hypotheses on the role of these cells in arthritis pathogenesis and opens up the way for further mechanistic studies. We show that the transformation of FLSs into arthritogenic cells occurs early in arthritis development. We also observed arthritogenic potential in FLSs isolated from contralateral non-arthritic joints in our monoarticular arthritis model. Long-lasting inflammation was not required for imprinting of arthritogenicity in FLSs since cells isolated from acute arthritic joints were fully competent to transfer arthritis. FLS transfer induced a chronic arthritis with recruitment of inflammatory cells and marked cartilage destruction. ResultsįLSs from AIA mice were able to transfer arthritis into recipient SCID mice. Their arthritogenic capacity was assessed by monitoring joint swelling and evaluation of histological parameters 70 to 100 days after transfer. MethodsįLSs were isolated, expanded in vitro, and transferred into knee joint cavities of severe combined immunodeficient (SCID) mice. To elucidate inducing mechanisms involved in this altered behavior, the arthritogenic potential of FLSs from murine antigen-induced arthritis (AIA) were investigated in a transfer model. Fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) are autonomously activated to maintain inflammation and joint destruction in co-transplantation models.
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