The mechanism of liraglutide on promoting osteogenesis via macrophages polarization under the inflammatory and oxidative stress in osteoporosis.

AIMS: Osteoporosis (OP), is mainly characterized by decreased bone mineral density and bone quality highly correlated with inflammatory and oxidative microenvironment. Liraglutide (Lira), as a glucagon-like peptide-1 receptor agonist, demonstrated an osteogenic effect. This research aims to explore the bidirectional regulatory effects of Lira on immunity and bone in osteoporosis. MATERIALS AND METHODS: The OP model was established by ovariectomy on 8w female C57BL/6J divided into the sham, OVX, OVX + Lira group (n = 30/group). The effects of Lira on inflammation, oxidative stress and bone regeneration on OP were evaluated by Micro CT and histological analysis. The mechanism of Lira on anti-inflammation and anti-oxidation was detected with the primary BMDMs, BMSCs, and MC3T3-E1 cells by WB, RT-PCR, immunofluorescence and RNA seq. KEY FINDINGS: Lira improves bone formation, regulates macrophage polarization and reduces inflammation and oxidative stress levels in OP mice. Lira inhibits the M1 macrophage polarization of BMDMs by the TNF pathway in primary cells of OP mice, and promoted the osteogenic differentiation of BMSCs. Lira promotes macrophage polarization toward M2 through the decreased CCL2, CXCL10, and NFKBIA in the TNF pathway in LPS-treated BMDMs. Lira reduces heme oxygenase-1 (HO-1) and 4-HNE expression in HO-treated MC3T3-E1 via macrophage, which induces Nrf2 nuclear translocation. The decreased cleaved caspase-3 and Bax/Bcl-2 indicated that the osteoblast apoptosis was inhibited by Lira. (*p < 0.05, **p < 0.01, ***p < 0.001). SIGNIFICANCE: Lira inhibits inflammation and oxidation through decreasing TNF-α pathway of macrophage and Nrf2 translocation of MC3T3-E1, that results in osteogenesis and anti-apoptosis in OP.