Pulsed electromagnetic fields activate a peripheral interoceptive pathway to suppress sympathetic Npy for osteogenesis.

Chronic stress-induced osteoporosis is a prevalent yet therapeutically challenging condition, with sympathetic overactivation as a key contributor. The dominant pathological mediator and strategies for its precise, non-invasive modulation remain unclear. Here, we identify sympathetic neuropeptide Y as a critical driver of this pathology. Using an unpredictable chronic mild stress model in male mice, we show that neuropeptide Y directly induces cellular senescence in bone marrow adipocytes, thereby impairing osteogenesis. Pulsed electromagnetic field treatment rescued bone loss in wild-type mice, but not in mice with sympathetic neuron-specific deletion of neuropeptide Y (ThCre;NPYfl/fl), demonstrating that neuropeptide Y suppression is required for pulsed electromagnetic field efficacy. Mechanistically, pulsed electromagnetic field action depends on intact sensory innervation and operates through the adipocyte neuropeptide Y receptor Y1R. We further delineate a novel peripheral circuit: pulsed electromagnetic field activates sensory nerves to trigger local release of semaphorin 3 A, which in turn directly suppresses sympathetic neuropeptide Y secretion within the bone marrow microenvironment-a mechanism validated by in vitro co-culture and semaphorin 3 A blockade. This sensory-sympathetic feedback loop functions autonomously, independent of central pathways. Our study reveals a local interoceptive mechanism by which pulsed electromagnetic field counteracts stress-induced osteoporosis, positioning peripheral neuropeptide Y -Y1R signaling as a precise target for neuromodulatory therapy.