title: Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts.
abstract: 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.
authors.affiliation: University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okada
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: 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
chemical_list: 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