Oncostatin M attenuates tumor necrosis factor-α-induced synthesis of macrophage-colony stimulating factor via suppression of Akt in osteoblasts.
Oncostatin M attenuates tumor necrosis factor-α-induced synthesis of macrophage-colony stimulating factor via suppression of Akt in osteoblasts.
复制标题
Oncostatin M 通过抑制成骨细胞中的 Akt 来减弱肿瘤坏死因子-α 诱导的巨噬细胞集落刺激因子的合成。
DOI：
10.1080/03008207.2022.2109468
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Tokuda H.
中科院分区：
文献类型：
--
作者：
Hioki T;Kuroyanagi G;Matsushima-Nishiwaki R;Kozawa O;Tokuda H.
骨巨噬细胞产生的抑瘤素M是白细胞介素6家族的一种细胞因子，与骨折愈合有关。成骨细胞分泌的巨噬细胞集落刺激因子（M-CSF）在破骨细胞生成中发挥重要作用。我们以前曾报道，肿瘤坏死因子-α（TNF-α），一种有效的骨吸收剂，刺激成骨样MC 3 T3-E1细胞中p44/p42丝裂原活化蛋白（MAP）激酶、Akt和p70 S6激酶的活化，并至少部分通过Akt诱导M-CSF的合成。我们研究了抑瘤素M是否影响TNF-α诱导的MC 3 T3-E1细胞M-CSF的合成及其机制。通过ELISA评估M-CSF释放。实时定量RT-PCR检测M-CSF mRNA表达水平。Western blot检测Akt、p44/p42 MAP激酶和p70 S6激酶的磷酸化。TNF-α诱导的M-CSFmRNA表达被抑瘤素M显著抑制。mTOR/p70 S6激酶抑制剂雷帕霉素对TNF-α释放M-CSF的影响不大。Oncostatin M显著降低TNF-α诱导的Akt和p44/p42 MAP激酶磷酸化。结论制瘤素M可抑制TNF-α刺激的成骨细胞M-CSF合成，其抑制作用可能发生在Akt和p44/p42 MAP激酶的上游，而对p70 S6激酶无影响。
BackgroundOncostatin M produced by osteal macrophages, a cytokine that belongs to the interleukin-6 family, is implicated in bone fracture healing. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts plays an important role in osteoclastogenesis. We have previously reported that tumor necrosis factor-α (TNF-α), a potent bone resorptive agent, stimulates the activation of p44/p42 mitogen-activated protein (MAP) kinase, Akt, and p70 S6 kinase in osteoblast-like MC3T3-E1 cells, and induces the synthesis of M-CSF at least in part via Akt.ObjectiveIn the present study, we investigated whether oncostatin M affects the TNF-α-induced M-CSF synthesis in MC3T3-E1 cells and the underlying mechanisms.MethodsClonal osteoblast-like MC3T3-E1 cells were treated with oncostatin M or rapamycin and then stimulated with TNF-α. M-CSF release was assessed by ELISA. M-CSF mRNA expression level was assessed by real-time RT-PCR. Phosphorylation of Akt, p44/p42 MAP kinase, and p70 S6 kinase was detected by Western blot analysis.ResultsOncostatin M dose-dependently reduced the TNF-α-stimulated M-CSF release. The expression of M-CSF mRNA induced by TNF-α was significantly suppressed by oncostatin M. Rapamycin, an inhibitor of mTOR/p70 S6 kinase, had little effect on the M-CSF release by TNF-α. Oncostatin M significantly reduced the TNF-α-induced phosphorylation of Akt and p44/p42 MAP kinase. However, the p70 S6 kinase phosphorylation by TNF-α was not affected by oncostatin M.ConclusionThese results strongly suggest that oncostatin M attenuates TNF-α-stimulated synthesis of M-CSF in osteoblasts, and the inhibitory effect is exerted at a point upstream of Akt and p44/p42 MAP kinase but not p70 S6 kinase.