Confinement prevents postmenopausal osteoporosis and obesity via nuclear mechanical remodeling

Postmenopausal osteoporosis (PMOP), affecting about half of postmenopausal women, is a major global health burden characterized by fragile bones and frequent comorbidity with obesity. Bone marrow mesenchymal stem cells (BMSCs) differentiation imbalance underpins PMOP pathogenesis and represents an attractive therapeutic target. Here, we demonstrate mechanically confining BMSCs to soft substrates mimicking physiological bone marrow stiffness completely suppresses adipogenic differentiation while inducing osteogenic differentiation. Mechanistically, confinement-induced elevation of nuclear envelope tension upregulates Lamin A/C expression, which in turn modulates Runx2 nuclear localization by activating histone acetylation via KAT2B, thereby directing BMSCs osteogenesis. Remarkably, FDA-approved deacetylation inhibitor Chidamide significantly enhances bone regeneration while concurrently suppressing obesity in a PMOP animal model, highlighting the significant therapeutic potential of nuclear mechanotransduction as a target for PMOP and obesity treatment. This work not only provides new insights into the mechanical regulation of bone homeostasis but also opens new avenues for the treatment of osteoporosis-related disorders.