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Original Article | Open Access

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

Jinlong Suo1,, Sihai Zou2,, Jinghui Wang3,, Yujiao Han3, Lingli Zhang3, Chenchen Lv3, Bo Jiang3, Qian Ren3, Long Chen3, Lele Yang3, Ping Ji2, Xianyou Zheng1( ), Ping Hu4,5,6,7( ), Weiguo Zou1,3 ( )
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
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031 Shanghai, China
Guangzhou Laboratory, No. 9 XingDaoHuan Road, Guanghzou International Bio lsland, 510005 Guangzhou, China
Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Shanghai, China
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China
Bio-Research Innovation Center, Shanghai Institute of Biochemistry and Cell Biology, Suzhou, China

These authors contributed equally: Jinlong Suo, Sihai Zou, Jinghui Wang

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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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Bone Research
Volume 10,
December 2022
Article number: 31
DOI: 10.1038/s41413-022-00202-3
Cite this article:
Suo J, Zou S, Wang J, et al. The RNA-binding protein Musashi2 governs osteoblast-adipocyte lineage commitment by suppressing PPARγ signaling. Bone Research, 2022, 10: 31. https://doi.org/10.1038/s41413-022-00202-3

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Received: 29 August 2020
Revised: 29 September 2021
Accepted: 08 January 2022
Published: 17 March 2022
© The Author(s) 2022

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