Suo Jinlong, Zou Sihai, Wang Jinghui, Han Yujiao, Zhang Lingli, Lv Chenchen, Jiang Bo, Ren Qian, Chen Long, Yang Lele, Ji Ping, Zheng Xianyou, Hu Ping, Zou Weiguo
Department of Orthopedic Surgery and Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 200233, Shanghai, China.
Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, 401147, Chongqing, China.
Bone Res. 2022 Mar 17;10(1):31. doi: 10.1038/s41413-022-00202-3.
Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells (BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2 (Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling. RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
衰老引起的骨质疏松症的特征是骨量减少和骨髓腔中脂肪细胞积聚。衰老过程中骨髓间充质干细胞（BMSC）成骨分化与脂肪生成之间的平衡是如何丧失的仍不清楚。在此，我们发现RNA结合蛋白Musashi2（Msi2）调节BMSC的谱系定向。Msi2通常在干细胞和肿瘤细胞中富集。我们发现，在BMSC的脂肪生成分化过程中其表达下调，而在成骨分化过程中上调。Msi2基因敲除小鼠表现出骨量减少，伴有大量骨髓脂肪细胞积聚，类似于衰老诱导的骨质疏松症。BMSC中Msi2的缺失导致脂肪细胞定向增加。转录谱分析显示，Msi2缺乏导致PPARγ信号增加。RNA相互作用蛋白免疫沉淀试验表明，Msi2可抑制关键脂肪生成因子Cebpα的翻译，从而抑制PPAR信号。此外，在小鼠衰老过程中Msi2的表达显著下降，表明衰老过程中Msi2功能下降导致骨髓中脂肪细胞异常积聚和骨质疏松症。因此，我们的结果为衰老相关的骨质疏松症提供了一种可能的生化机制，表明调节Msi2功能可能有益于骨衰老的治疗。
