Demethylation of PPWD1 by KDM4A Inhibits Osteogenic Differentiation of BMSCs from Postmenopausal Osteoporosis by Inhibiting the Integrin/FAK Signaling

Background: Postmenopausal osteoporosis (PMOP) is a metabolic bone disease characterized by an increase in calcium absorption and bone mass due to a decrease in estrogen levels. This leads to frequent osteoporotic fracture among the elderly. The decreased osteogenic ability of bone marrow mesenchymal stromal cells (BMSCs) plays a key role in PMOP. The present study aimed to explore the underlying mechanism of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) on the osteogenic differentiation of BMSCs in PMOP rats.Methods: In this study, a PMOP model was established, and BMSCs were collected and cultured. The gene characteristics and expression patterns of PPWD1 were analyzed using a molecular database search. The expressions of PPWD1 were valued in different marrow mesenchymal stromal cells (MSCs) of PMOP. Furthermore, the function and mechanism of PPWD1 in BMSCs were furtherly explored both in vitro and in vivo.Results: We found that PPWD1 was significantly upregulated in BMSCs of PMOP, and it negatively regulated the osteogenic differentiation of BMSCs. In contrast, integrin/focal adhesion kinase (FAK) inhibition effectively suppressed the osteogenesis induced by PPWD1 knockdown both in vivo and in vitro. Moreover, our data demonstrated that lysine demethylase 4A (KDM4A) effectively enhances the transcription of PPWD1 by reducing the methylation of histone H3K9me (H3K9) at the PPWD1 promoter.Conclusions: The present study identified a new function of PPWD1 and shed new light on the molecular mechanism that underlies osteogenic differentiation of BMSCs in PMOP.