Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Nakano
Kazuhisa
K
University of Occupational and Environmental Health, Kitakyushu, Japan.
Okada
Yosuke
Y
Saito
Kazuyoshi
K
Tanaka
Yoshiya
Y
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001862:Bone Resorption / Q000503:physiopathology; D002352:Carrier Proteins / Q000032:analysis*; D002478:Cells, Cultured; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis*; D010003:Osteoarthritis / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis; D013583:Synovial Membrane / Q000166:cytology*; D015854:Up-Regulation
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017468:Receptors, Fibroblast Growth Factor; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C036090:heparin proteoglycan; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D018799:Intercellular Adhesion Molecule-1; D006493:Heparin; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1