<scp>MicroRNA</scp> ‐128‐3p Deficiency Alleviates Bone Loss in Age‐Related Osteoporosis via Activation of Canonical Wnt Signaling

MicroRNA-128-3p (miR-128-3p) has emerged as a crucial regulator of the aging process and age-associated disorders. Recent research highlights the vital role of miR-128-3p in osteoclast (OC) differentiation and the progression of osteoporosis following ovariectomy. Nonetheless, the mechanism by which miR-128-3p influences osteoblast (OB)-mediated bone formation and contributes to bone loss associated with aging is poorly understood. The present investigation began with an analysis of human bone samples, in which we observed that the age-related miR-128-3p increase was negatively correlated with bone formation. In addition, miR-128-3p expression decreased during OB differentiation. Next, we found that OB miR-128-3p conditional deletion (cKO, miR-128-3p^Ob-/-) markedly increased bone mass by increasing bone formation. We also revealed that global knockout of miR-128-3p (KO, miR-128-3p^-/-) controlled skeletal homeostasis. Further in vitro studies confirmed that miR-128-3p deletion in OBs stimulates osteoblastogenesis; its inhibition in MC3T3-E1 cells gave similar results. Mechanistically, miR-128-3p regulated osteoblastogenesis via disheveled-2 (Dvl2)-mediated canonical Wnt signaling. Finally, osteoblastic miR-128-3p deficiency prevented age-related bone loss in mice. In summary, our results establish the role of miR-128-3p in OB differentiation and bone formation, thereby providing insight into potential diagnostic and therapeutic targets in age-related osteoporosis.