Huang Xianzhe, Jie Shuo, Li Wenzhao, Liu Chan
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, PR China.
International Medical Department, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, PR China.
Cell Death Discov. 2023 May 8;9(1):150. doi: 10.1038/s41420-023-01422-0.
Postmenopausal osteoporosis (PMOP) brings a lot of inconvenience to patients and serious economic burden to society. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays vital role in the process of PMOP treatment. However, the functional mechanism remains unclear. In this study, GATA4, MALAT1 and KHSRP were downregulated in bone tissues of PMOP patients, while NEDD4 was overexpressed. Through functional experiments, GATA4 overexpression strikingly accelerated osteogenic differentiation of BMSCs and promoted bone formation in vitro and in vivo, while these effects were dramatically reversed after MALAT1 silence. Intermolecular interaction experiments confirmed that GATA4 activated the transcription of MALAT1, which could form a 'RNA-protein' complex with KHSRP to decay NEDD4 mRNA. NEDD4 promoted the degradation of Runx1 by ubiquitination. Moreover, NEDD4 silencing blocked the inhibitory effects of MALAT1 knockdown on BMSCs osteogenic differentiation. In sum up, GATA4-activated MALAT1 promoted BMSCs osteogenic differentiation via regulating KHSPR/NEDD4 axis-regulated RUNX1 degradation, ultimately improving PMOP.
绝经后骨质疏松症（PMOP）给患者带来诸多不便，并给社会造成沉重的经济负担。骨髓间充质干细胞（BMSCs）的成骨分化在PMOP治疗过程中起着至关重要的作用。然而，其功能机制仍不清楚。在本研究中，PMOP患者骨组织中GATA4、MALAT1和KHSRP表达下调，而NEDD4过表达。通过功能实验，GATA4过表达显著加速了BMSCs的成骨分化，并在体内外促进了骨形成，而MALAT1沉默后这些作用显著逆转。分子间相互作用实验证实，GATA4激活MALAT1的转录，其可与KHSRP形成“RNA-蛋白质”复合物以降解NEDD4 mRNA。NEDD4通过泛素化促进Runx1的降解。此外，NEDD4沉默阻断了MALAT1敲低对BMSCs成骨分化的抑制作用。综上所述，GATA4激活的MALAT1通过调节KHSPR/NEDD4轴调控的RUNX1降解促进BMSCs成骨分化，最终改善PMOP。
