Administration of SB239063 Ameliorates Ovariectomy-Induced Bone Loss via Suppressing Osteoclastogenesis in Mice
Administration of SB239063 Ameliorates Ovariectomy-Induced Bone Loss via Suppressing Osteoclastogenesis in Mice
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SB239063 通过抑制破骨细胞生成改善卵巢切除引起的骨质流失
DOI：
10.3389/fphar.2019.00900
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发表时间：
2019-08-15
影响因子：
5.6
通讯作者：
Zhao, Fengdong
中科院分区：
文献类型：
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作者：
Huang, Bao;Wang, Jiasheng;Zhao, Fengdong
破骨细胞形成和功能的激活对于溶骨性疾病（如骨质疏松症）的发展至关重要。RANKL（核因子 - κB受体激活剂配体）激活NF - κB（核因子κB）、MAPK（丝裂原活化蛋白激酶）和NFATc1（活化T细胞的核因子，细胞质1）信号通路以诱导破骨细胞生成。在本研究中，我们证明了SB239063，一种p38特异性抑制剂，通过抑制MEF2C（肌细胞增强因子2C）的磷酸化并随后导致MEF2C通过泛素化降解，从而抑制破骨细胞生成和骨吸收。MEF2C的敲低由于c - Fos表达降低而损害破骨细胞形成。此外，MEF2C可直接结合到c - Fos的启动子区域以启动其转录。有趣的是，MEF2C或c - Fos的过表达均可部分挽救SB239063对破骨细胞生成的抑制作用。此外，体内数据证明SB239063在LPS（脂多糖）和OVX（卵巢切除）诱导的小鼠骨质流失中也起到预防作用。总之，我们的结果表明SB239063可作为溶骨性疾病的一种潜在治疗方法，并且一种新的p38/MEF2C/c - Fos轴对于破骨细胞生成至关重要。
Activation of osteoclast formation and function is crucial for the development of osteolytic diseases such as osteoporosis. RANKL (receptor activator of nuclear factor-kappa B ligand) activates NF-kappa B (nuclear factor kappa B), MAPK (mitogen-activated protein kinase), and NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) signaling pathways to induce osteoclastogenesis. In this study, we demonstrated that SB239063, a p38-specific inhibitor, suppressed osteoclastogenesis and bone resorption via inhibiting phosphorylation of MEF2C (myocyte enhancer factor 2C) and subsequently leading to MEF2C degradation by ubiquitination. Knockdown of MEF2C impaired osteoclast formation due to decreased c-Fos expression. Furthermore, MEF2C can directly bind to the promoter region of c-Fos to initiate its transcription. Interestingly, overexpression of either MEF2C or c-Fos can partially rescue the inhibitory effect of SB239063 on osteoclastogenesis. In addition, in vivo data proved that SB239063 also played a preventive role in both LPS (lipopolysaccharide)-and OVX (ovariectomy)-induced bone loss in mice. In conclusion, our results show that SB239063 can be a potential therapy for osteolytic diseases, and a novel p38/MEF2C/c-Fos axis is essential for osteoclastogenesis.