SREBF2 drives osteoporosis by divergently regulating Hippo/YAP-mediated adipogenesis and BMP/Smad-mediated osteogenesis in bone marrow stromal cells

PURPOSE: Osteoporosis results from an imbalance in bone remodeling, often driven by the maldifferentiation of bone marrow stromal cells (BMSCs) toward adipogenesis rather than osteogenesis. Sterol regulatory element-binding transcription factor 2 (SREBF2) is a master regulator of cholesterol metabolism. Given the interplay between lipid metabolism and bone homeostasis, this study aimed to investigate the role of SREBF2 in regulating BMSC fate and to elucidate its underlying mechanisms in osteoporosis pathogenesis. MATERIALS AND METHODS: SREBF2 expression was analyzed via bioinformatics of osteoporosis datasets and validated in clinical samples. Its function was validated in vitro using shRNA knockdown in human BMSCs, assessing osteogenic (ALP, ARS staining) and adipogenic (Oil Red O staining) differentiation. Signaling mechanisms were explored using Western blot and rescue experiments with SIS3 (BMP inhibitor) and YAP overexpression. In vivo efficacy was evaluated in an ovariectomized (OVX) mouse model. RESULTS: SREBF2 was significantly elevated in osteoporotic patients. Knockdown of SREBF2 in BMSCs enhanced osteogenesis and suppressed adipogenesis. Mechanistically, SREBF2 depletion inhibited Hippo signaling and activated BMP/Smad signaling. The pro-osteogenic effect was reversed by SIS3, while the anti-adipogenic effect was rescued by YAP overexpression. In vivo, SREBF2 knockdown ameliorated OVX-induced bone loss, improving microstructural parameters and restoring signaling balance. CONCLUSIONS: SREBF2 promotes osteoporosis by activating Hippo/YAP to drive adipogenesis while inhibiting BMP/Smad to suppress osteogenesis in BMSCs. Targeting SREBF2 is a promising therapeutic strategy.