Piezo1 activates Wnt5a/FZD4 signaling to promote osteogenesis and mitigates age-associated bone loss.

With aging, the responsiveness of bone tissue to mechanical loading progressively declines, leading to altered bone homeostasis and continuous bone loss. Piezo1, a recently identified mechanosensitive calcium channel, plays a critical role in bone development, formation, and homeostatic regulation in a load-dependent manner. The Wnt signaling pathway is also essential for mechanotransduction in bone cells; however, the precise role of Piezo1 in maintaining osteogenic homeostasis remains unclear. Here, through transcriptomic analysis of bone tissues from young and aged mice, we found that both Piezo1 and Wnt signaling pathways were significantly downregulated in aged mice compared with young controls. Further investigations revealed that the expression of Piezo1 and Wnt5a/FZD4 decreased with age in osteoblasts. Loss of Piezo1 in osteoblasts exacerbated age-related bone loss and suppressed the Wnt5a/FZD4 signaling cascade. Conversely, activation of Piezo1 enhanced osteogenesis and stimulated Wnt5a/FZD4 signaling, while treatment with a Wnt5a agonist partially rescued the impaired osteogenic capacity caused by Piezo1 deficiency. Moreover, Wnt5a activation modestly alleviated osteoporosis in aged mice. Collectively, our study provides the first systematic evidence that the mechanoreceptor Piezo1, via downstream Wnt5a/FZD4 signaling, plays a central role in skeletal mechanoadaptation and age-associated bone loss. These findings highlight the activation of Wnt5a downstream of Piezo1 as a potential therapeutic strategy for preventing bone loss due to impaired mechanotransduction during aging.