TMEM18 inhibits osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells by inactivating β-catenin
TMEM18 inhibits osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells by inactivating β-catenin
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DOI：
10.1016/j.yexcr.2019.07.004
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发表时间：
2019-10-01
影响因子：
3.7
通讯作者：
Yang, Tieyi
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Wang, Hongyan;Yang, Tieyi
跨膜蛋白18（transmembrane protein 18，Tmem 18）是一个与肥胖相关的基因，在脂肪形成中起重要作用，但其在骨髓间充质干细胞（bone marrow-derived mesenchymal stem cells，BMSCs）成骨分化中的作用尚不清楚。在这项研究中，我们发现Tmem 18在大鼠BMSCs成骨诱导后显著下调。TMEM 18过表达显著下调骨特异性基因，包括碱性磷酸酶（Alp），Runt相关转录因子2（Runx 2），骨钙素（Ocn）和骨桥蛋白（Opn），并减少体外矿物质沉积和ALP活性的数量，而TMEM 18的敲除产生相反的结果。体内试验还表明，TMEM 18敲低的BMSC在大鼠颅骨缺损模型中具有增加的骨形成潜力。机制分析表明，TMEM 18过表达降低β-catenin的表达，而TMEM 18敲低增强β-catenin的表达，并促进其核转位。由于TMEM 18基因敲低对大鼠BMSCs成骨分化的积极作用被β-连环蛋白下调所减弱。总之，这些结果表明，TMEM 18通过β-连环蛋白的失活在BMSC的成骨分化中起抑制作用。
Transmembrane protein 18 (Tmem18) is an obesity-associated gene essential for adipogenesis; however, its function in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is still unclear. In this study, we found that Tmem18 was significantly downregulated in rat BMSCs after osteogenic induction. TMEM18 overexpression remarkably downregulated osteo-specific genes including alkaline phosphatase (Alp), Runt-related transcription factor 2 (Runx2), osteocalcin (Ocn), and osteopontin (Opn), and reduced the number of mineral deposits and ALP activity in vitro, whereas knockdown of Tmem18 yielded the opposite results. In vivo assays also indicated that TMEM18 knockdown BMSCs have an increased bone formation potential in a rat model of calvarial defects. Analyses of the mechanism suggested that TMEM18 overexpression decreased beta-catenin expression, whereas the TMEM18 knockdown enhanced beta-catenin expression and promoted its nuclear translocation. The positive effects on osteogenic differentiation of rat BMSCs owing to the TMEM18 knockdown were attenuated by beta-catenin downregulation. Taken together, these results indicate that TMEM18 plays an inhibitory role in osteogenic differentiation of BMSCs via inactivation of beta-catenin.