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
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
复制标题
DOI：
10.2220/biomedres.43.41
复制
发表时间：
2022-01-01
影响因子：
1.2
通讯作者：
Tokuda, Haruhiko
中科院分区：
文献类型：
--
作者：
Doi, Tomoaki;Hioki, Tomoyuki;Tokuda, Haruhiko
骨折是反映老龄化社会的重要创伤，也是急诊医学和骨科常见的创伤。抑癌素M是一种由骨巨噬细胞产生的炎性细胞因子，在骨折愈合过程中起着至关重要的作用。由成骨细胞分泌的巨噬细胞集落刺激因子(M-CSF)在破骨细胞的形成过程中起重要作用，其分泌受转化生长因子-β(TGF-β)的刺激。本研究旨在阐明抑瘤素M对转化生长因子-β诱导成骨样MC3T3-EL细胞合成M-CSF的影响及其机制。抑瘤素M可抑制转化生长因子-β刺激的巨噬细胞集落刺激因子的释放和mRNA的表达。SMAD3抑制剂SIS3、p38 MAP激酶抑制剂SB203580、MEK1/2抑制剂PD98059和SAPK/JNK抑制剂SP600125显著抑制M-CSF的释放。抑制转化生长因子-β诱导的p44/p42和SAPK/JNK的磷酸化，但不影响Smad3和p38的磷酸化。抑瘤素M抑制转化生长因子-β刺激的血管内皮生长因子的释放和转化生长因子-β诱导的血管内皮细胞生长因子的mRNA表达。这些结果有力地表明，oncoatin M下调成骨细胞中p44/p42和SAPK/JNK上游的转化生长因子-β信号，但不下调Smad2/3和p38MAP激酶的上游信号，从而导致M-CSF合成的抑制。我们的发现可能为加速骨折愈合进程提供一种新的治疗策略。
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-beta (TGF-beta). The aim of this study is to elucidate the effects of oncostatin M on the TGF-beta-induced M-CSF synthesis in osteoblast-like MC3T3-El cells and the underlying mechanisms. Oncostatin M attenuated the TGF-beta-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-beta-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-beta-stimulated vascular endothelial growth factor (VEGF) release and the TGF-beta-induced mRNA expressions of VEGF. These results strongly suggest that oncostatin M downregulates TGF-beta 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.