Xiao Hao, Wu Zhixin, Jiang Tao, Zhu Jiayong, Zhou Siqi, Xie Xingkui, Wang Hui, Chen Liaobin
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China; Joint Disease Research Center of Wuhan University, Wuhan 430071, China.
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Joint Disease Research Center of Wuhan University, Wuhan 430071, China.
Biochem Pharmacol. 2023 Sep;215:115722. doi: 10.1016/j.bcp.2023.115722. Epub 2023 Jul 29.
Osteoporotic osteoarthritis is primarily associated with low subchondral bone mass. However, the mechanisms and therapeutic targets of osteoporotic osteoarthritis caused by prenatal dexamethasone exposure (PDE) in offspring remain unclear. In this study, pregnant Wistar rats were injected with dexamethasone to obtain bone tissue from fetal and postnatal rat offspring for analysis. Bone marrow mesenchymal stem cells (BMSCs) were isolated in vitro to elucidate the underlying molecular mechanisms. We determined in vivo that PDE reduced subchondral bone mass in adult female rat offspring, which originated from dysplasia of the subchondral bone. PDE led to a continuous increase in miR-6215 expression, accompanied by a decrease in FERM domain-containing protein 6 (FRMD6) expression. In vitro, dexamethasone upregulated miR-6215 expression through the glucocorticoid receptor, thereby inhibiting FRMD6 expression, promoting the translocation of yes-associated protein 1 (YAP1) into the nucleus of BMSCs, and downregulating downstream osteogenic marker genes. Finally, the rAAV-miR-6215 inhibitor rescued the low subchondral bone mass and osteoarthritis susceptibility caused by PDE in rat offspring. In conclusion, increased expression of miR-6215 mediates low subchondral bone mass caused by PDE through FRMD6/YAP1 signaling. Therefore, miR-6215 is a promising therapeutic target for PDE-induced low subchondral bone mass in offspring.
骨质疏松性骨关节炎主要与软骨下骨量低有关。然而，产前地塞米松暴露（PDE）导致后代发生骨质疏松性骨关节炎的机制和治疗靶点仍不清楚。在本研究中，给怀孕的Wistar大鼠注射地塞米松，以获取胎儿和出生后大鼠后代的骨组织进行分析。体外分离骨髓间充质干细胞（BMSCs）以阐明潜在的分子机制。我们在体内确定，PDE降低了成年雌性大鼠后代的软骨下骨量，这源于软骨下骨发育异常。PDE导致miR-6215表达持续增加，同时含FERM结构域蛋白6（FRMD6）表达降低。在体外，地塞米松通过糖皮质激素受体上调miR-6215表达，从而抑制FRMD6表达，促进Yes相关蛋白1（YAP1）转位到BMSCs细胞核中，并下调下游成骨标记基因。最后，rAAV-miR-6215抑制剂挽救了PDE导致的大鼠后代软骨下骨量低和骨关节炎易感性。总之，miR-6215表达增加通过FRMD6/YAP1信号传导介导PDE引起的软骨下骨量低。因此，miR-6215是PDE诱导的后代软骨下骨量低的一个有前景的治疗靶点。
