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<p>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<sup>-/-</sup> 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.</p>

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Targeting miR-337 mitigates disuse-induced bone loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • 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

摘要

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.