Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Northern
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Bone and Bones / metabolism
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Cathepsin K
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Cathepsins / biosynthesis
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Cell Survival
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Cells, Cultured
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Cyclooxygenase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / metabolism*
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Flavonoids / pharmacology
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Immunoblotting
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Kinetics
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Male
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Matrix Metalloproteinase 2 / biosynthesis
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Nitrobenzenes / pharmacology
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Osteoblasts / metabolism
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Osteoclasts / metabolism*
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Phosphorylation
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Precipitin Tests
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Protein-Tyrosine Kinases*
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RNA, Messenger / metabolism
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Rabbits
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 2
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Receptor, Fibroblast Growth Factor, Type 3
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Receptor, Fibroblast Growth Factor, Type 4
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Receptors, Fibroblast Growth Factor / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Sulfonamides / pharmacology
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Time Factors
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Tyrosine / metabolism
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Up-Regulation
Substances
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Flavonoids
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Nitrobenzenes
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RNA, Messenger
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Receptors, Fibroblast Growth Factor
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Sulfonamides
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Fibroblast Growth Factor 2
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Tyrosine
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Fgfr1 protein, mouse
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Fgfr2 protein, mouse
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Fgfr3 protein, mouse
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Fgfr4 protein, mouse
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 2
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Receptor, Fibroblast Growth Factor, Type 3
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Receptor, Fibroblast Growth Factor, Type 4
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Cathepsins
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Cathepsin K
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Ctsk protein, mouse
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Matrix Metalloproteinase 2
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one