Abstract
IntroductionInflammatory destructive arthritis, like rheumatoid arthritis (RA), is characterized by invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, leading to progressive joint destruction. Because fibroblast activation protein alpha (FAP) has been associated with cell migration and cell invasiveness, we studied the function of FAP in joint destruction in RA.MethodsExpression of FAP in synovial tissues and fibroblasts from patients with osteoarthritis (OA) and RA as well as from wild-type and arthritic mice was evaluated by immunohistochemistry, fluorescence microscopy and polymerase chain reaction (PCR). Fibroblast adhesion and migration capacity was assessed using cartilage attachment assays and wound-healing assays, respectively. For in vivo studies, FAP-deficient mice were crossed into the human tumor necrosis factor transgenic mice (hTNFtg), which develop a chronic inflammatory arthritis. Beside clinical assessment, inflammation, cartilage damage, and bone erosion were evaluated by histomorphometric analyses.ResultsRA synovial tissues demonstrated high expression of FAP whereas in OA samples only marginal expression was detectable. Consistently, a higher expression was detected in arthritis SF compared to non-arthritis OA SF in vitro. FAP-deficiency in hTNFtg mice led to less cartilage degradation despite unaltered inflammation and bone erosion. Accordingly, FAP−/− hTNFtg SF demonstrated a lower cartilage adhesion capacity compared to hTNFtg SF in vitro.ConclusionsThese data point to a so far unknown role of FAP in the attachment of SF to cartilage, promoting proteoglycan loss and subsequently cartilage degradation in chronic inflammatory arthritis.
Highlights
Inflammatory destructive arthritis, like rheumatoid arthritis (RA), is characterized by invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, leading to progressive joint destruction
fibroblast activation protein alpha (FAP) is highly expressed in RA synovial tissues and fibroblasts To assess whether FAP may be involved in the pathology of RA, we first investigated whether a higher expression of FAP in synovial tissues as well as in SF of RA patients is evident
In line with these data, SF obtained from RA patients demonstrated a higher expression of FAP transcripts compared to SF from OA patients (Figure 1F) and a higher expression was observed in rheumatoid arthritis synovial fibroblasts (RASF) compared to osteoarthritis synovial fibroblasts (OASF), as reflected by significantly higher fluorescence levels (Figure 1C and D)
Summary
Inflammatory destructive arthritis, like rheumatoid arthritis (RA), is characterized by invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, leading to progressive joint destruction. Rheumatoid arthritis (RA) is an autoimmune disease that primarily affects the joints and that is characterized by chronic inflammation and progressive cartilage and bone destruction [1]. Synovial inflammation and hyperplasia as well as invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, all are hallmarks of RA [2]. We studied the in vivo role of FAP in joint destruction in a human tumor necrosis factor (TNF) transgenic (hTNFtg) mouse model of RA, characterized by progressive cartilage and bone loss [12]
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