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
Summary
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have