MiR-1292 Targets FZD4 to Regulate Senescence and Osteogenic Differentiation of Stem Cells in TE/SJ/Mesenchymal Tissue System via the Wnt/β-catenin Pathway

With the expansion of the elderly population, age-related osteoporosis and the resulting bone loss have become a significant health and socioeconomic issue. In Triple Energizer (TE)/San Jiao (SJ)/mesenchymal tissue system, mesenchymal stem cell (MSC) senescence, and impaired osteogenesis are thought to contribute to age-related diseases such as osteoporosis. Therefore, comprehending the molecular mechanisms underlying MSC senescence and osteogenesis is essential to improve the treatment of bone metabolic diseases. With the increasing role of miRNAs in MSC aging and osteogenic differentiation, we need to understand further how miRNAs participate in relevant mechanisms. In this study, we observed that the expression of miR-1292 was augmented during cellular senescence and lessened with osteogenesis in human adipose-derived mesenchymal stem cells (hADSCs). miR-1292 expression was positively correlated with senescence markers and negatively associated with bone formation markers in clinical bone samples. Overexpression of miR-1292 notably accelerated hADSC senescence and restrained osteogenesis, whereas its knockdown decreased senescence and enhanced osteogenic differentiation. Furthermore, miR-1292 upregulation inhibited ectopic bone formation <i>in vivo</i>. Mechanistically, FZD4 was identified as a potential target of miR-1292. Downregulation of FZD4 phenocopied the effect of miR-1292 overexpression on hADSC senescence and osteogenic differentiation. Moreover, the impact of miR-1292 suppression on senescence and osteogenesis were reversed by the FZD4 knockdown. Pathway analysis revealed that miR-1292 regulates hADSC senescence and osteogenesis through the Wnt/β-catenin signaling pathway. Thus, TE/SJ/mesenchymal tissue system is the largest organ composed of various functional cells derived from mesoderm, responsible for maintaining homeostasis and regulating cell senescence. miR-1292 might serve as a novel therapeutic target for the prevention and treatment of osteoporosis or other diseases related to bone metabolism and aging.