Rheumatoid arthritis (RA) is characterized by progressive joint destruction. The aim of this study was to clarify the relevance of RA synovial fibroblasts (RASFs) and fibroblast growth factor 2 (FGF-2), which is produced abundantly by RASFs, to the osteoclastogenesis and bone resorption in RA.
Synovial fibroblasts were prepared from the synovial tissues of 10 patients with active RA and 7 patients with osteoarthritis (OA). The expression of RANKL, intercellular adhesion molecule 1 (ICAM-1), FGF receptor 1 (FGFR-1), and heparan sulfate proteoglycan (HSPG) on synovial fibroblasts was measured by FACScan. Osteoclast formation in cocultures of RASFs and peripheral blood mononuclear cells (PBMCs) was evaluated by tartrate-resistant acid phosphatase staining and a pit-formation assay using dentin slices.
FGF-2 induced the expression of both RANKL and ICAM-1 on RASFs more so than on OA synovial fibroblasts (OASFs). FGF-2–induced up-regulation of RANKL and ICAM-1 was inhibited by anti–FGF-2 antibody. Although FGFR-1 was equally expressed on RASFs and OASFs, HSPG was highly expressed on RASFs. Up-regulation of RANKL by FGF-2 on RASFs was diminished by the removal of heparan sulfate with heparitinase. Osteoclast formation from PBMCs induced by RASFs was inhibited by the addition of either heparitinase, anti–ICAM-1 antibody, anti–FGF-2 antibody, or osteoprotegerin. FGF-2–induced RANKL on RASFs and osteoclast formation were suppressed by an inhibitor of ERK.
FGF-2 was transferred to FGFR-1 through binding to HSPG, which is characteristically expressed on RASFs, resulting in RANKL- and ICAM-1–mediated maturation of osteoclasts via ERK activation. Thus, we propose that FGF-2 not only augments the proliferation of RASFs, but also is involved in osteoclast maturation, which leads to bone destruction in RA.