Department of Orthopaedics, Gongli Hospital of Pudong New Area, Shanghai, China.
Ningxia Medical University, Yinchuan, China.
Exp Cell Res. 2019 Oct 1;383(1):111491. doi: 10.1016/j.yexcr.2019.07.004. Epub 2019 Jul 6.
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 β-catenin expression, whereas the TMEM18 knockdown enhanced β-catenin expression and promoted its nuclear translocation. The positive effects on osteogenic differentiation of rat BMSCs owing to the TMEM18 knockdown were attenuated by β-catenin downregulation. Taken together, these results indicate that TMEM18 plays an inhibitory role in osteogenic differentiation of BMSCs via inactivation of β-catenin.
跨膜蛋白 18（Tmem18）是一种与肥胖相关的基因，对脂肪生成至关重要；然而，其在骨髓间充质干细胞（BMSCs）成骨分化中的功能尚不清楚。在本研究中，我们发现 Tmem18 在大鼠 BMSCs 成骨诱导后显著下调。TMEM18 过表达显著下调成骨特异性基因，包括碱性磷酸酶（Alp）、Runt 相关转录因子 2（Runx2）、骨钙素（Ocn）和骨桥蛋白（Opn），并减少体外矿化沉积物的数量和 ALP 活性，而 Tmem18 的敲低则产生相反的结果。体内实验也表明 TMEM18 敲低的 BMSCs 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，TMEM18 过表达降低 β-连环蛋白表达，而 TMEM18 敲低则增强 β-连环蛋白表达并促进其核易位。TMEM18 敲低对大鼠 BMSCs 成骨分化的正向作用因 β-连环蛋白下调而减弱。综上所述，这些结果表明 TMEM18 通过失活β-连环蛋白在 BMSCs 的成骨分化中发挥抑制作用。
