S100a8-Ifn-ⅰ Signaling Modulates Osteogenesis/Adipogenesis In Osteoporosis Bone Homeostasis

This study aims to investigate the regulatory mechanism by which S100A8 modulates osteogenic and adipogenic differentiation in osteoporotic BMSCs (OP-BMSCs), explore therapeutic targets for enhancing bone formation and maintaining bone homeostasis. Female SD rats (6-month-old) underwent bilateral ovariectomy to establish osteoporosis, approved by the Institutional Ethics Committee (No.20231201-002). Primary BMSCs were isolated from tibiae for osteogenic/adipogenic differentiation assays. S100A8 was overexpressed in OP-BMSCs via lentivirus and knocked down in control BMSCs using siRNA. Followed by analysis of osteogenic/adipogenic marker genes/proteins and staining with ALP, Alizarin Red, and Oil Red O to investigate regulatory effects . High-throughput sequencing was conducted to identify key pathways and downstream targets . Finally, AAV-mediated S100A8 overexpression in the femur of osteoporotic rats was performed, and bone mass and marrow adiposity were re-evaluated using Micro-CT and immunohistochemistry . (1)OP-BMSCs exhibit reduced osteogenesis but enhanced adipogenesis. Overexpression of S100A8 in OP-BMSCs rescued osteogenesis and suppressed adipogenesis, while its knockdown in control BMSCs exacerbated adipogenesis and inhibited osteogenesis. (2)Transcriptomics and experimental data revealed that S100A8 modulates the balance between osteogenic and adipogenic differentiation in OP-BMSCs via IFN-Ⅰ interferon signaling pathway. (3)AAV-mediated S100A8 overexpression reversed bone loss and marrow adiposity, restoring bone homeostasis. This study firstly demonstrates that S100A8 modulates BMSCs fate via IFN-Ⅰsignaling, offering a novel therapeutic target for osteoporosis-related bone loss. Its dual role in balancing skeletal remodeling aligns providing translational insights for alveolar bone regeneration.