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.

由衰老引起的骨质疏松症的特征是骨髓腔内骨量减少和脂肪细胞堆积。骨髓间充质干细胞 (BMSCs) 的成骨细胞生成和脂肪生成之间的平衡是如何随着衰老而丧失的仍不清楚。在这里，我们发现 RNA 结合蛋白 Musashi2 ( Msi2 ) 调节 BMSC 谱系定型。Msi2通常富含干细胞和肿瘤细胞。我们发现其表达在成脂分化过程中下调，在骨髓间充质干细胞成骨分化过程中上调。Msi2敲除小鼠的骨量减少，骨髓脂肪细胞大量积累，类似于衰老诱导的骨质疏松症。Msi2的耗尽在 BMSCs 中导致脂肪细胞承诺增加。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测定表明，Msi2可以抑制关键的脂肪生成因子Cebpα的翻译，从而抑制 PPAR 信号传导。此外，小鼠衰老过程中Msi2的表达显着降低，表明衰老过程中Msi2功能下降导致骨髓脂肪细胞异常积累和骨质疏松症。因此，我们的结果为衰老相关的骨质疏松症提供了推定的生化机制，表明调节Msi2功能可能有利于骨老化的治疗。