RAD51 promotes osteogenic differentiation and inhibits DNA damage in osteoporosis though regulating cGAS-STING signaling pathway.

INTRODUCTION: Osteoporosis (OP) represents a metabolic bone disorder characterized by reduced bone density and increased fracture susceptibility, primarily caused by an imbalance between bone resorption and formation. Osteogenic differentiation plays a critical role in OP, as it promotes bone formation processes. RAD51, a crucial gene encoding a protein essential for homologous recombination repair of DNA double-strand breaks, is central to maintaining genomic stability and ensuring accurate DNA repair. Previous investigations conducted by our research team have suggested the involvement of RAD51 in the pathogenesis of OP. The objective of this study was to explore the signaling pathways associated with RAD51. METHODS: MC3T3-E1 cells were induced to undergo osteogenic differentiation and exposed to a microgravity environment to simulate OP-like conditions. Furthermore, an ovariectomized (OVX) mouse model was established to mimic OP. Osteogenic differentiation was evaluated through Alizarin Red S staining for calcium deposition and alkaline phosphatase (ALP) staining to assess ALP activity. DNA damage was quantified using the comet assay, while protein expression profiles were analyzed via Western blot. RESULTS: Experimental results showed a significant downregulation of RAD51 expression in OP models. Notably, RAD51 overexpression promoted osteoblast differentiation and mitigated DNA damage in these models. Mechanistic studies further revealed that RAD51 suppresses activation of the cGAS-STING signaling pathway, which has been shown to negatively regulate osteoblast differentiation. In OVX mice, RAD51 overexpression mitigated bone loss, promoted osteoblast differentiation, and reduced DNA damage. CONCLUSION: RAD51 facilitated osteogenic differentiation and attenuated DNA damage in OP by modulating the cGAS-STING signaling pathway, offering a potential novel therapeutic target for OP treatment.