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

Abstract

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 in vivo. 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.

The Masquelet technique: Current concepts, animal models, and perspectives

“…Blocking myostatin (a ligand that binds to members of the TGF-ß superfamily) by the application of follistatin increased the osteogenic potential of adipose-derived stem cells (Wallner et al, 2019). The micro-RNA 1292 (a regulator of Wnt/β-catenin pathway) inhibited osteoblastic differentiation and increased the senescence of human adipose-derived MSCs in vitro and promoted ectopic bone formation in vivo (Fan et al, 2018). The micro-RNA146a-5p was expressed in CD14 + monocytes, and this expression was correlated with differentiation into osteoclasts and with bone resorption in patients (Lin et al, 2019).…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…In vivo MSC senescence implies reduced osteogenic capacity, thus contributing to age-related diseases such as osteoporosis. In ASCs, miR-1292 was found to positively regulate cell senescence through the wingless-related integration site (Wnt)/β-catenin signalling pathway and targeting frizzled 4 receptor (FZD4), thus emerging as a potential target to treat osteoporosis [117]. Moreover, Liu et al [118] demonstrated that the loss of osteogenic potential in aged BM-MSCs is mediated by p53 increase through the miR-17 pathway.…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…Meanwhile, TGF-β accelerated cellular senescence by promoting the miR-29-mediated loss of H4K20me3. Fan et al [65] observed the role of miR-1292 in cellular senescence of human adipose-derived mesenchymal stem cells (hADSCs). They found that FZD4 downregulation acted as a potential target of miR-1292, leading to overexpression of miR-1292, which promoted hADSC aging and osteogenic differentiation.…”