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

Abstract

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.

The effect of rotative stress on CAII, FAS, FASL, OSCAR, and TRAP gene expression in osteoclasts

“…In summary, based on the findings of this study as well as previous studies, we conclude that: (1) functions of signaling factors may be induced by stress; (2) there was an adjustment in the signaling pathway because of similar stress patterns (Suzuki et al, 1996; Lee and Kim, 2003; Kawaguchi et al, 2004; Nakamura et al, 2005; Tanaka et al, 2006).…”

Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: Estrogen receptor dependent or independent pathways of raloxifene

“…Therefore, MAF gene induced by only raloxifene treatment in our present study may be involved in the process of regulating cell growth or cell-cell interaction in human normal osteoblasts but it awaits further investigations for clarification. The expression of GAS6 mRNA transcript was also reported in mice osteoblasts, osteoclasts, and bone marrow cells [36]. GAS6 protein is a secreted protein originally identified as the ligand for the tyrosine kinase receptor Axl, and Gas6 was reported to be able to protect NIH3T3 cell apoptosis induced by growth factor depletion [37].…”

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

“…Growth factors, such as fibroblast growth factor-2 (FGF-2), growth arrest-specific gene 6 (Gas6), and tumor necrosis factor-α (TNF-α), stimulate mature osteoclast function and survival through ERK activation [ 32 , 33 ]. ERK is transiently activated during transforming growth factor-β1 (TGF-β1)-induced apoptosis of osteoclasts differentiated from human umbilical cord blood monocytes, via the activation of caspase-9 and upregulation of the pro-apoptotic protein Bim [ 34 ].…”