2831-LB: GLP-1R in JBMMSCs Suppressed Jaw Bone Osteoporosis via Modulating PKA/STAT3/TET3/SHP2/ß-catenin Signaling–Induced Osteoblast Differentiation

Introduction and Objective: This study aimed to investigate the molecular mechanisms by which Semaglutide modulates JBMMSC osteogenic differentiation to ameliorate jaw osteoporosis in ovariectomized (OVX) rats. Methods: Bioinformatics analysis of GEO data predicted signaling nodes. Primary JBMMSCs were isolated from rat jaw bone and characterized by flow cytometry. A rat jaw osteoporosis model was established by OVX. Micro-CT and H&E staining evaluated bone microarchitecture and therapeutic effects of transplanted JBMMSCs with/without Semaglutide preconditioning, and SHP2 involvement. In vitro, JBMMSCs were treated with Semaglutide under osteogenic/adipogenic conditions; differentiation was assessed by Alizarin Red S and Oil Red O staining. Western blot quantified osteogenic (RUNX2, OCN) and adipogenic (PPARγ) markers, and signaling molecules (p-GLP-1R, p-PKA, p-STAT3, TET3, total SHP2, p-SHP2, β-catenin). Results: Micro-CT revealed that transplantation of Semaglutide-preconditioned JBMMSCs alleviated OVX-induced bone loss, partially reversed by SHP2 inhibition, indicating SHP2's critical role. In vitro, Semaglutide promoted osteogenic mineralization and suppressed adipogenesis. Mechanistically, Semaglutide activated GLP-1R, leading to sequential phosphorylation of PKA and STAT3, upregulation of TET3, modulation of SHP2 phosphorylation, and subsequent β-catenin stabilization, driving osteogenic gene transcription. Rescue experiments confirmed the hierarchical PKA/STAT3/TET3/SHP2/β-catenin axis in osteoblast differentiation. Conclusion: For the first time, these findings demonstrate that GLP-1R activation by Semaglutide in JBMMSCs attenuates jaw osteoporosis via the PKA/STAT3/TET3/SHP2/β-catenin pathway promoting osteogenic differentiation. This study provides novel molecular insights into the osteoprotective effects of GLP-1RAs and supports Semaglutide in stem cell-based strategies for osteoporotic bone regeneration. Disclosure H. Liu: None. Funding National Natural Science Foundation of China (82170892)