Gu Huimin, Yu Wenhui, Feng Pei, Zeng Chenying, Cao Qian, Chen Fenglei, Wang Ziming, Shen Huiyong, Wu Yanfeng, Wang Shan
Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, P. R. China.
Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, P. R. China.
Cell Mol Life Sci. 2025 Apr 7;82(1):149. doi: 10.1007/s00018-025-05684-y.
Increased adipogenic differentiation and decreased osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) along with slow self-renewal are pivotal causes for decreased bone formation in senile osteoporosis. Circular RNAs (circRNAs) play important roles in cell proliferation and differentiation, and are closely related to osteoporosis. Whether circRNAs orchestrate the adipo-osteogenic balance and the proliferation of BMSCs in osteoporosis remains unclear. We found in this study that circSTX12 was abnormally upregulated in bone sections from osteoporosis patients and in BMSCs from aged mice, as well as in later-generation human BMSCs in culture. Knockdown of circSTX12 in BMSCs resulted in enhanced osteogenesis, decreased adipogenesis, and increased proliferation capacity; circSTX12 overexpression had the opposite effect. RNA pull-down and mass spectrometry revealed the interactions between circSTX12 with CBL and LMO7. At the molecular level, circSTX12 regulated cell fate in BMSCs by competitively binding to CBL, reducing the ubiquitination-mediated degradation of MST1 and thereby activating the Hippo pathway, a key regulator of adipo-osteogenic balance. Knockdown of circSTX12 promoted the nuclear localization of YAP. In addition, our findings suggest that LMO7 mediates circSTX12-induced BMSCs proliferation by regulating the transcription of CCNA2, CCNH, and CCND1. In vivo, injection of antisense oligonucleotides (ASOs) to knockdown circSTX12 promoted bone formation in aged mice. Our results provide evidence for circSTX12 as a regulator of adipo-osteogenic differentiation and proliferation of BMSCs through binding to CBL and LMO7, respectively. Targeting circSTX12 may be a novel approach for osteoporosis treatment.
骨髓间充质干细胞（BMSCs）的成脂分化增加和成骨分化减少，以及自我更新缓慢，是老年性骨质疏松症中骨形成减少的关键原因。环状RNA（circRNAs）在细胞增殖和分化中起重要作用，且与骨质疏松症密切相关。circRNAs是否在骨质疏松症中协调BMSCs的成脂-成骨平衡和增殖仍不清楚。我们在本研究中发现，circSTX12在骨质疏松症患者的骨切片、老年小鼠的BMSCs以及培养的传代人BMSCs中异常上调。敲低BMSCs中的circSTX12导致成骨增强、脂肪生成减少和增殖能力增加；circSTX12过表达则产生相反的效果。RNA下拉和质谱分析揭示了circSTX12与CBL和LMO7之间的相互作用。在分子水平上，circSTX12通过竞争性结合CBL来调节BMSCs中的细胞命运，减少泛素化介导的MST1降解，从而激活Hippo通路，这是成脂-成骨平衡的关键调节因子。敲低circSTX12促进了YAP的核定位。此外，我们的研究结果表明，LMO7通过调节CCNA2、CCNH和CCND1的转录来介导circSTX12诱导的BMSCs增殖。在体内，注射反义寡核苷酸（ASOs）敲低circSTX12可促进老年小鼠的骨形成。我们的结果为circSTX12分别通过与CBL和LMO7结合作为BMSCs成脂-成骨分化和增殖的调节因子提供了证据。靶向circSTX12可能是一种治疗骨质疏松症的新方法。
