Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase.
We previously reported that fibroblast growth factor-2 (FGF-2) acts not only on osteoblasts to stimulate osteoclastic bone resorption indirectly but also on mature osteoclasts directly. In this study, we investigated the mechanism of this direct action of FGF-2 on mature osteoclasts using mouse and rabbit osteoclast culture systems. FGF-2 stimulated pit formation resorbed by isolated rabbit osteoclasts moderately from low concentrations (>/=10(-12) m), whereas at high concentrations (>/=10(-9) m) it showed stimulation on pit formation resorbed by unfractionated bone cells very potently. FGF-2 (>/=10(-12) m) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. Among FGF receptors (FGFR1 to 4) only FGFR1 was detected on isolated mouse osteoclasts, whereas all FGFRs were identified on mouse osteoblasts. FGF-2 (>/=10(-12) m) up-regulated the phosphorylation of cellular proteins, including p42/p44 mitogen-activated protein (MAP) kinase, and increased the kinase activity of immunoprecipitated FGFR1 in mouse osteoclasts. The stimulation of FGF-2 on mouse and rabbit osteoclast functions was abrogated by PD-98059, a specific inhibitor of p42/p44 MAP kinase. These results strongly suggest that FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.
Chikazu
D
D
Departments of Orthopaedic Surgery and Oral and Maxillofacial Surgery, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-8655, Japan.
Hakeda
Y
Y
Ogata
N
N
Nemoto
K
K
Itabashi
A
A
Takato
T
T
Kumegawa
M
M
Nakamura
K
K
Kawaguchi
H
H
D000818:Animals; D015152:Blotting, Northern; D001842:Bone and Bones / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000096:biosynthesis; D002470:Cell Survival; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015151:Immunoblotting; D007700:Kinetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009578:Nitrobenzenes; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D013449:Sulfonamides; D016222:Fibroblast Growth Factor 2; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D014443:Tyrosine; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C496366:Fgfr3 protein, mouse; C496372:Fgfr4 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020778:Matrix Metalloproteinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one