Simulated microgravity-driven mechanical unloading rescues PIEZO1-overexpression-induced growth plate ossification and retards adolescent idiopathic scoliosis.

Adolescent Idiopathic Scoliosis (AIS) progresses via excessive concave-endplate compressive stress and PIEZO1 overexpression-induced vertebral growth plate chondrocyte degeneration. Though microgravity-mediated mechanical unloading is traditionally linked to musculoskeletal harm, we explored its therapeutic potential for AIS. We integrated clinical observations, in vivo models, and in vitro experiments: Clinical anti-gravity skull traction (mechanical unloading) reduced a severe AIS patient's Cobb angle. In a scoliosis mouse model, 10 h/day traction suspension delayed deformity. In vitro, 100 kPa pressure overload upregulated PIEZO1 in chondrocytes, while simulated microgravity reversed this, inhibiting ossification and matrix degeneration. Mouse tail compression elevated PIEZO1 and accelerated ossification, which tail suspension reversed. PIEZO1 agonist Yoda1 promoted chondrocyte osteogenic differentiation, confirming PIEZO1's pathological role. This study shows simulated microgravity-mediated mechanical unloading alleviates AIS by inhibiting PIEZO1, repurposing microgravity from a "pathological factor" to a non-invasive AIS therapy, bridging aerospace medicine and orthopedics.