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

Jinlong Suo; Sihai Zou; Jinghui Wang; Yujiao Han; Lingli Zhang; Chenchen Lv; Bo Jiang; Qian Ren; Long Chen; Lele Yang; Ping Ji; Xianyou Zheng; Ping Hu; Weiguo Zou

doi:10.1038/s41413-022-00202-3

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

Bone Res. 2022 Mar 17;10(1):31. doi: 10.1038/s41413-022-00202-3.

Authors

Jinlong Suo^#¹, Sihai Zou^#², Jinghui Wang^#³, Yujiao Han³, Lingli Zhang³, Chenchen Lv³, Bo Jiang³, Qian Ren³, Long Chen³, Lele Yang³, Ping Ji², Xianyou Zheng⁴, Ping Hu^{5

6

7

8}, Weiguo Zou^{9

10}

Affiliations

¹ Department of Orthopedic Surgery and Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 200233, Shanghai, China.
² 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.
³ 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.
⁴ Department of Orthopedic Surgery and Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 200233, Shanghai, China. zhengxianyou@126.com.
⁵ Guangzhou Laboratory, No. 9 XingDaoHuan Road, Guanghzou International Bio lsland, 510005, Guangzhou, China. hup@sibcb.ac.cn.
⁶ Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China. hup@sibcb.ac.cn.
⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China. hup@sibcb.ac.cn.
⁸ Bio-Research Innovation Center, Shanghai Institute of Biochemistry and Cell Biology, Suzhou, China. hup@sibcb.ac.cn.
⁹ Department of Orthopedic Surgery and Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 200233, Shanghai, China. zouwg94@sibcb.ac.cn.
¹⁰ 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. zouwg94@sibcb.ac.cn.

^# Contributed equally.

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.

Abstract

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