Semaglutide blocks osteoblast ferroptosis in diabetic periodontitis by modulating Wnt5a/Ror2/p38 MAPK pathway

Patients with Type 2 diabetes mellitus (T2DM) frequently suffer from severe periodontitis, which leads to accelerated alveolar bone loss. A key contributor to osteoblast dysfunction in diabetic conditions is ferroptosis, an iron-dependent form of regulated cell death. The non-canonical Wnt5a/Ror2 signaling pathway is known to regulate inflammation and bone metabolism. While Semaglutide, a long-acting GLP-1 receptor agonist, is recognized for its metabolic benefits, its potential to modulate this pathway and protect osteoblasts from ferroptosis in the context of diabetic periodontitis has been unclear.

Researchers investigated semaglutide's effects on osteoblasts in vitro and in vivo. For in vitro studies, MC3T3-E1 osteoblasts were exposed to high glucose plus palmitic acid (HGHP) to simulate a diabetic microenvironment. Osteoblast proliferation, migration, differentiation, mineralization, and ferroptosis were assessed using EDU, Transwell, ALP and ARS staining, qPCR, Western blotting, ROS, Fe2⁺, and lipid peroxidation assays. The mechanistic role of Wnt5a/Ror2/p38 MAPK signaling was explored using Wnt5a siRNA and a p38 MAPK agonist. In vivo, T2DM mice with ligature-induced periodontitis were treated with semaglutide. Alveolar bone integrity and ferroptosis-related markers were evaluated via H&E, immunohistochemistry (for OPN, GPX4), and 4-HNE immunofluorescence.

High glucose plus palmitic acid (HGHP) significantly induced osteoblast ferroptosis, increased oxidative stress, and impaired osteogenic function in vitro. Treatment with Semaglutide effectively restored osteoblast proliferation and osteogenic capacity, while also attenuating oxidative stress and ferroptosis. The study identified that Wnt5a was upregulated by HGHP, and its silencing notably reduced ferroptosis and improved osteogenesis. Mechanistically, semaglutide suppressed the HGHP-induced activation of the Wnt5a/Ror2/p38 MAPK pathway. Conversely, activating p38 MAPK blunted semaglutide's protective effects on osteoblasts. > In the in vivo model, semaglutide treatment in T2DM periodontitis mice significantly reduced periodontal inflammation and osteoblast ferroptosis, indicating a protective role against bone loss. These findings collectively demonstrate semaglutide's ability to mitigate osteoblast dysfunction and ferroptosis under diabetic conditions.