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

Abstract

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.

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Funding

National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)(81725010)

the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB19000000. W Z is a scholar of ‘the National Science Fund for Distinguished Young Scholars’ (NSFC) [81725010].

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Science (XDA16020400 to PH), Ministry of Science and Technology of China (2017YFA0102700 to PH), the National Natural Science Foundation of China (91649104 and 31671536 to PH), Space Medical Experiment Project of China Manned Space Program (HYZHXM01017 to PH) and Science and Technology of Commission of Shanghai Municipal (17JC1400901 to PH), Peak Disciplines (Type IV) of Institution of High Learning in Shanghai.

This work was supported by the fellowship of China Postdoctoral Science Foundation (2021TQ0207) and the ‘Basic research project of Shanghai Sixth People’s Hospital’ (ynqn202102).