HIRA promotes osteogenic differentiation of BMSCs and ameliorates osteoporosis by mediating M2 polarization of macrophages through the YAP1/β-catenin pathway

Impaired macrophage polarization is a key factor exacerbating osteoporosis (OP), influencing bone metabolism via modulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Histone cell cycle regulator (HIRA), an epigenetic regulator, is downregulated in OP. However, its role in modulating macrophage polarization and BMSCs osteogenic differentiation remains unclear. Bone marrow-derived macrophages (BMDMs) and BMSCs were extracted from the bone marrow of SD rats, and identified using staining and flow cytometry. An ovariectomized (OVX) mouse model was established, and HIRA protein was detected via Western blot. A co-culture system of BMDMs and BMSCs was established, and BMDMs were transfected with an HIRA overexpression plasmid. Cytokine levels were measured by ELISA kits, bone structure was assessed via micro-CT, and histopathological staining evaluated femoral tissue pathology, calcium deposition, and osteoclast counts. The levels of proteins associated with osteogenic differentiation, osteoclast differentiation, macrophage polarization, and the YAP1/β-catenin pathway were detected using Western blot. HIRA is downregulated in BMSCs treated with dexamethasone and in the femoral tissues of OVX mice. Overexpression of HIRA effectively raised M2 polarization markers and reduced M1 polarization markers in BMDMs, and promoted BMSCs osteogenic differentiation. Following HIRA overexpression in OVX mice, femoral tissue damage was significantly reduced, osteoclast numbers decreased, and bone metabolic imbalance improved. Furthermore, HIRA overexpression also activated the YAP1/β-catenin axis in the femoral tissue of OVX mice, thereby suppressing bone loss and promoting macrophage M2 polarization. HIRA promotes M2 polarization of macrophages by activating the YAP1/β-catenin pathway, thereby enhancing BMSC osteogenic differentiation and ultimately reducing bone loss in OVX mice.