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.

Highlights

  • We previously reported that fibroblast growth factor-2 (FGF-2) acts on osteoblasts to stimulate osteoclastic bone resorption indirectly and on mature osteoclasts directly

  • Because previous reports have shown that the bone resorptive effect of FGF-2 is mediated at least in part by COX-2 induction in osteoblastic cells (18, 20 – 22), the contribution of COX-2 to the direct action was examined by adding NS-398 (1 ␮M), a specific inhibitor of COX-2, to the culture of isolated osteoclasts

  • These actions were mediated by the autophosphorylation of FGFR1, the only subtype of FGFRs expressed on osteoclasts, and the subsequent phosphorylation of cellular proteins, including p42/ p44 mitogen-activated protein (MAP) kinase

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Summary

Introduction

We previously reported that fibroblast growth factor-2 (FGF-2) acts on osteoblasts to stimulate osteoclastic bone resorption indirectly and on mature osteoclasts directly. Because previous reports have shown that the bone resorptive effect of FGF-2 is mediated at least in part by COX-2 induction in osteoblastic cells (18, 20 – 22), the contribution of COX-2 to the direct action was examined by adding NS-398 (1 ␮M), a specific inhibitor of COX-2, to the culture of isolated osteoclasts.

Results
Conclusion
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