Osteoclastic bone resorption through receptor tyrosine kinase and extracellular signal-regulated kinase signaling in mature osteoclasts.

It has recently been suggested that signaling through receptor tyrosine kinases (RTKs) expressed on mature osteoclasts is involved in osteoclastic bone resorption. This study investigated the role and mechanism of two major RTKs expressed on mature osteoclasts, fibroblast growth factor receptor type 1 (FGFR1) and Tyro 3. Among the FGF receptors (FGFR1-4), only FGFR1 was detected on isolated mouse osteoclasts, while all FGFRs were identified on mouse osteoblasts. Tyro 3 was seen only in mature osteoclasts among bone cells. FGF-2 moderately stimulated pit formation by isolated rabbit osteoclasts at low concentrations (>==10(-12) M), whereas at high concentrations (>==10(-9) M) it strongly stimulated pit formation by unfractionated bone cells. Gas6, the ligand of Tyro 3, was expressed ubiquitously in bone cells and stimulated osteoclast function to form resorbed pits on a dentine slice. Both FGF-2 and Gas6 upregulated the phosphorylation of cellular proteins, including extracellular signal-regulated kinase (ERK), and increased the kinase activity of immunoprecipitated FGFR1 and Tyro 3, respectively, in mouse osteoclasts. The stimulation of these cytokines on mouse and rabbit osteoclast functions was abrogated by PD98059, a specific inhibitor of ERK. These results strongly suggest that these cytokines act directly on mature osteoclasts through the activation of RTKs and ERK, causing the stimulation of bone resorption.