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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.

The RNA-binding protein Musashi2 governs osteoblast-adipocyte lineage commitment by suppressing PPARγ signaling