Oncostatin M reduces the synthesis of macrophage-colony stimulating factor stimulated by TGF-β via suppression of p44/p42 MAP kinase and JNK in osteoblasts.

Abstract

Bone fracture is an important trauma frequently encountered into emergency medicine as well as orthopedics reflecting an aging society. Oncostatin M, an inflammatory cytokine produced by osteal macrophages, has been considered to play a crucial role in fracture healing. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts is essential in osteoclastgenesis, and the secretion is stimulated by transforming growth factor-β (TGF-β). The aim of this study is to elucidate the effects of oncostatin M on the TGF-β-induced M-CSF synthesis in osteoblast-like MC3T3-E1 cells and the underlying mechanisms. Oncostatin M attenuated the TGF-β-stimulated M-CSF release and the mRNA expressions. SMAD3 inhibitor SIS3, p38 MAP kinase inhibitor SB203580, MEK1/2 inhibitor PD98059, and SAPK/JNK inhibitor SP600125 significantly suppressed the M-CSF release. Oncostatin M suppressed the TGF-β-induced phosphorylation of p44/p42 MAP kinase and SAPK/JNK, but failed to affect the phosphorylation of SMAD3 and p38 MAP kinase. Oncostatin M attenuated the TGF-β-stimulated vascular endothelial growth factor (VEGF) release and the TGF-β-induced mRNA expressions of VEGF. These results strongly suggest that oncostatin M downregulates TGF-β signaling upstream of p44/p42 MAP kinase and SAPK/JNK, but not SMAD 2/3 and p38 MAP kinase, in osteoblasts, leading to the attenuation of M-CSF synthesis. Our findings might provide a new therapeutic strategy for the acceleration of fracture healing process.