Autophagic damage in senescent bone marrow mesenchymal stromal cells: Impact on Piezo1 expression during osteoporosis...

Osteoporosis is a major health challenge, particularly in postmenopausal women. Bone marrow mesenchymal stromal cells (BMSCs) are crucial for maintaining bone homeostasis by differentiating into osteoblasts and adipocytes. However, in the osteoporotic microenvironment, aging and estrogen deficiency lead to oxidative stress, impairing BMSC function and promoting senescence. Piezo1, a mechanosensitive calcium-permeable ion channel highly expressed in BMSCs, translates mechanical cues into pro-osteogenic signals. This study aimed to investigate the interplay between autophagy, Piezo1 expression, and BMSC senescence in osteoporosis, and explore the therapeutic potential of modulating the autophagy-Piezo1 axis. We observed that Piezo1 expression was downregulated in the bone tissues of patients with osteoporosis and ovariectomized (OVX) mice, accompanied by an increase in senescence-associated markers in BMSCs. Oxidative stress reduced Piezo1 expression and promoted BMSC senescence, shifting differentiation toward adipogenic rather than osteogenic lineages. Autophagic flux was impaired in senescent BMSCs, and activating autophagy via rapamycin restored Piezo1 expression, alleviated senescence, and rebalanced osteogenic/adipogenic differentiation. Mechanistically, inhibiting the mTOR/S6K pathway enhanced autophagy and Piezo1 expression. Rapamycin treatment increased bone mass and improved bone microarchitecture in OVX mice by promoting Piezo1 expression and suppressing senescence markers. Our findings highlight the critical role of autophagy in maintaining Piezo1 expression and BMSC function, suggesting that targeting the autophagy-Piezo1 axis may offer a novel therapeutic strategy for osteoporosis management.