Oncostatin M suppresses bone morphogenetic protein‐4‐induced osteoprotegerin synthesis in MC3T3‐E1 osteoblast‐like cells: p70 S6 kinase attenuation

Evidence is accumulating that osteal macrophages, in addition to bone‐resorbing osteoclasts and bone‐forming osteoblasts, participate vitally in bone remodeling process. Oncostatin M (OSM), an inflammatory cytokine belonging to interleukin‐6 superfamily, is recognized as an essential factor secreted by osteal macrophages to orchestrate bone remodeling. Osteoprotegerin (OPG) produced by osteoblasts regulates osteoclastogenesis. We have reported that bone morphogenetic protein‐4 (BMP‐4) stimulates OPG synthesis in MC3T3‐E1 osteoblast‐like cells, and that SMAD1/5/8(9), p38 mitogen‐activated protein kinase (MAPK), and p70 S6 kinase are involved in the OPG synthesis. The present study aims to investigate the effect of OSM on the synthesis of OPG stimulated by BMP‐4 in osteoblasts. OSM suppressed the release and the mRNA expression of OPG upregulated by BMP‐4 in MC3T3‐E1 cells. Neither the BMP‐4‐induced phosphorylation of SMAD1/5/9 nor that of p38 MAPK was affected by OSM. On the other hand, the phosphorylation of p70 S6 kinase stimulated by BMP‐4 was considerably suppressed by OSM. These results strongly suggest that OSM suppresses the BMP‐4‐stimulated OPG synthesis via inhibition of the p70 S6 kinase‐mediated pathway in osteoblast‐like cells. Significance Statement Oncostatin M (OSM), a cytokine of the interleukin‐6 superfamily, modulates bone remodeling. Osteoprotegerin (OPG) secreted from osteoblasts regulates osteoclastogenesis. We previously showed that bone morphogenetic protein‐4 (BMP‐4) activates SMAD1/5/8(9), p38 mitogen‐activated protein kinase, and p70 S6 kinase, resulting in OPG synthesis in osteoblast‐like MC3T3‐E1 cells. In the present study, we investigated the effects of OSM on the BMP‐4‐induced synthesis of OPG in these cells. Our results strongly suggest that OSM suppresses OPG synthesis by inhibiting the p70 S6 kinase‐mediated pathway in osteoblasts.