Why does exercise slow the age-related loss of bone mineral density leading to osteoporosis? Researchers here find a critical role for mechanotransduction, the sensing of physical forces placed upon a cell, such as pressure or mechanical stress. Specifically the mechanosensor Piezo1 is triggered in mesenchymal stem cells in the bone marrow, and the subsequent response of this cell population acts to reduce inflammation, reduce fat cell generation in bone marrow, and thus allow the specialized cell populations working on bone extracellular matrix structures to better maintain a healthy bone mineral density. This opens the door to the development of therapies that can mimic this effect of exercise by triggering Piezo1 or downstream pathways.
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.
Importantly, our findings also indicate that Piezo1 invalidation abolishes exercise-induced benefits on bone volume and marrow adiposity, suggesting that Piezo1 senses physiological mechanical stress (presumably shear stress and compressive forces) in the bone marrow to regulate BMMSC fate decision. 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.
Link: https://doi.org/10.1038/s41392-025-02455-w
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