Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase

J Biol Chem. 2000 Oct 6;275(40):31444-50. doi: 10.1074/jbc.M910132199.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Bone and Bones / metabolism
  • Cathepsin K
  • Cathepsins / biosynthesis
  • Cell Survival
  • Cells, Cultured
  • Cyclooxygenase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fibroblast Growth Factor 2 / metabolism*
  • Flavonoids / pharmacology
  • Immunoblotting
  • Kinetics
  • Male
  • Matrix Metalloproteinase 2 / biosynthesis
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitrobenzenes / pharmacology
  • Osteoblasts / metabolism
  • Osteoclasts / metabolism*
  • Phosphorylation
  • Precipitin Tests
  • Protein-Tyrosine Kinases*
  • RNA, Messenger / metabolism
  • Rabbits
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, Fibroblast Growth Factor, Type 4
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Time Factors
  • Tyrosine / metabolism
  • Up-Regulation

Substances

  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • Nitrobenzenes
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • Sulfonamides
  • Fibroblast Growth Factor 2
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Tyrosine
  • Fgfr1 protein, mouse
  • Fgfr2 protein, mouse
  • Fgfr3 protein, mouse
  • Fgfr4 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, Fibroblast Growth Factor, Type 4
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Cathepsins
  • Cathepsin K
  • Ctsk protein, mouse
  • Matrix Metalloproteinase 2
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one