Piezo1 transduces mechanical signals to inhibit osteoclast fusion and coordinate bone homeostasis

Osteoclasts originate from bone marrow–derived macrophages, and their maturation relies on fusion of pre-osteoclasts into mature osteoclasts that maintain bone homeostasis. Previous studies established that mechanical signals regulate osteoblast activity in bone homeostasis, although whether such signals regulate bone homeostasis by acting on osteoclasts remains unclear. Herein, membrane tension decreased during pre-osteoclast fusion, accompanied by reduced Piezo1. This suggests that mechanical stimulation inhibits fusion of monocytes into osteoclasts through Piezo1. Piezo1-knockout monocytes ( CTSK ^Cre ; Piezo1 ^fl/fl ) attenuated the anabolic effect of exercise on bone mass in vivo, whereas shear stress inhibited osteoclast fusion in vitro. Piezo1 activation elevated E-cadherin, which anchors Merlin. This led to hyperactivation of the Yes-associated protein (YAP) signaling pathway, subsequently activating TAX1BP1 and suppressing NF-κB signaling as well as osteoclast differentiation and maturation. Thus, physical exercise activates a Piezo1–E-cadherin–Merlin–YAP axis that prevents osteoclast fusion, presenting a druggable mechanotransduction pathway for osteoporosis.