2. Academic Validation
  3. Piezo1 activation suppresses bone marrow adipogenesis to prevent osteoporosis by inhibiting a mechanoinflammatory autocrine loop

Piezo1 activation suppresses bone marrow adipogenesis to prevent osteoporosis by inhibiting a mechanoinflammatory autocrine loop

  • Signal Transduct Target Ther. 2025 Oct 28;10(1):357. doi: 10.1038/s41392-025-02455-w.
Baile Wang # 1 2 3,  Jie Liu # 4 5 6,  Qin Wang 4 5 6,  Malika Arhatte 7,  Lai Yee Cheong 4 5,  Edyta Glogowska 7,  Xue Jiang 4 5 6,  Sookja Kim Chung 4 8,  Leigang Jin 4 5 6,  Qianxing Hu 4 5 6,  Yu Wang 4 9,  Eric Honoré 10 11,  Aimin Xu 12 13 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. blwong@connect.hku.hk.
  • 2 Department of Medicine, The University of Hong Kong, Hong Kong, China. blwong@connect.hku.hk.
  • 3 Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong, China. blwong@connect.hku.hk.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
  • 5 Department of Medicine, The University of Hong Kong, Hong Kong, China.
  • 6 Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong, China.
  • 7 Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut national de la santé et de la recherche médicale, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, France.
  • 8 Faculty of Medicine; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
  • 9 Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China.
  • 10 Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut national de la santé et de la recherche médicale, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, France. honore@ipmc.cnrs.fr.
  • 11 Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China. honore@ipmc.cnrs.fr.
  • 12 State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. amxu@hku.hk.
  • 13 Department of Medicine, The University of Hong Kong, Hong Kong, China. amxu@hku.hk.
  • 14 Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong, China. amxu@hku.hk.
  • 15 Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China. amxu@hku.hk.
  • # Contributed equally.
PMID: 41145414 DOI: 10.1038/s41392-025-02455-w
Abstract

With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation. Mice with a specific Piezo1 invalidation in BMMSCs exhibit osteoporosis and marrow adiposity, together with resistance to the beneficial effects of exercise on bone health. Accordingly, Piezo1-deficient BMMSCs in vitro preferentially differentiate into adipocytes rather than osteoblasts. Invalidation of Piezo1 in BMMSCs enhances the autocrine activation of CCR2 by Ccl2, which further induces lipocalin-2 (Lcn2) production via NF-κB activation, thereby promoting adipocyte differentiation. Conversely, Piezo1 opening induces Klf2 expression through CaMKII, preventing c-Jun activation, Ccl2 production and bone marrow adipogenesis. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.

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