Targeting miR-337 mitigates disuse-induced bone loss

Jiao Li; Ding Ma; Chunxue Zhang; Xueling Zheng; Ruihan Hao; Bin Zuo; Fei Xiao; Yang Li; Yuhang Liu; Zhouyi Duan; Yao Xiong; Orion R Fan; Wenmin Zhu; Liming Dai; Bingjun Zhang; Yi Eve Sun; Xiaoling Zhang

doi:10.1038/s41421-025-00822-z

Targeting miR-337 mitigates disuse-induced bone loss

Cell Discov. 2025 Aug 26;11(1):71. doi: 10.1038/s41421-025-00822-z.

Authors

Jiao Li^#^{1

2}, Ding Ma^#³, Chunxue Zhang^#⁴, Xueling Zheng², Ruihan Hao¹, Bin Zuo¹, Fei Xiao¹, Yang Li¹, Yuhang Liu⁵, Zhouyi Duan¹, Yao Xiong⁴, Orion R Fan⁴, Wenmin Zhu⁴, Liming Dai^{1

6}, Bingjun Zhang^{1

6}, Yi Eve Sun⁷, Xiaoling Zhang^{8

9}

Affiliations

¹ Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Cell Biology, Zunyi Medical University, Zunyi, Guizhou, China.
³ Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. san-martin@sjtu.edu.cn.
⁴ Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁵ Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ National Facility for Translational Medicine (Shanghai), Shanghai, China.
⁷ Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. yi.eve.sun@gmail.com.
⁸ Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. xlzhang@shsmu.edu.cn.
⁹ National Facility for Translational Medicine (Shanghai), Shanghai, China. xlzhang@shsmu.edu.cn.

^# Contributed equally.

Abstract

Disuse-induced bone loss occurs in long-term bed-ridden patients and in astronauts during spaceflight. The underlying mechanisms are poorly understood. In a rodent model of disuse-induced bone loss (called hindlimb unloading (HU)), we observed that decreased numbers of leptin receptor (LepR) positive mesenchymal stem cells (MSCs) in adult bone marrow, contribute to bone loss. MicroRNA-337-3p (miR-337) was upregulated in MSCs upon HU and inhibited MSC proliferation by directly targeting IRS-1 to suppress the PI3kinase-Akt-mTOR pathway. Piezo1 was the upstream receptor for sensing mechanical stress and regulated miR-337 through the Hippo-YAP signaling pathway. Remarkably, the knockout of miR-337 significantly attenuated HU-induced, but not ovariectomy-induced, bone loss by increasing MSC proliferation and osteogenesis. Finally, the transplantation of miR-337^-/- MSCs into wild-type HU mice was sufficient to mitigate bone loss. These findings reveal the cellular and molecular mechanisms underlying disuse-induced bone loss and highlight a feasible therapeutic strategy to prevent disuse- or microgravity-induced bone loss on Earth and during spaceflight.

Abstract

Grants and funding