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.
Highlights
In traditional Chinese medicine (TCM), one fundamental San Jiao connect to be one Qi, protecting human body’, yet essential concept is the Triple Energizer (TE) or San and that the ‘San Jiao is not a true Fu without structure but Jiao (SJ) which states that ‘the upper, middle and lower having a function’
To compare the osteogenic differentiation potential during cell senescence, human adipose-derived mesenchymal stem cells (hADSCs) of P4 and P15 were cultured in osteogenic induction medium and assessed by Alkaline phosphatase (ALP) staining at day 4 and alizarin red staining at day 15
The mesenchymal stem cell (MSC) system consists of all mesodermderived functional cells at different stages of embryonic development, including postembryonic subtotipotent stem cells and progenitor cells covering all subsets of MSCs, such as CXCL12-abundant reticular (CAR) cells and pericytes [35]
Summary
In traditional Chinese medicine (TCM), one fundamental San Jiao connect to be one Qi, protecting human body’, yet essential concept is the Triple Energizer (TE) or San and that the ‘San Jiao is not a true Fu without structure but Jiao (SJ) which states that ‘the upper, middle and lower having a function’. TE/SJ/mesenchymal tissue system is involved in the stem cell proliferation, differentiation, senescence, and immune surveillance, as well as regulation of tissue regeneration and metabolism balance. Elucidating the molecular processes that control MSC senescence and osteogenesis is vital to develop valid therapies for osteoporosis and other age-associated bone metabolic diseases. How the specific factors implicated in this process orchestrate to regulate the senescence and osteogenic differentiation of MSCs remain elusive. MiRNAs are recognized as important regulators of various biological processes, including cell proliferation, migration, differentiation, apoptosis, and tissue development [2022]. MiR-1292 was found to enhance hADSC senescence and suppress osteogenic differentiation in vitro and delay bone formation in vivo by targeting FZD4 via the Wnt/β-catenin pathway. MiR1292/FZD4 might serve as a novel therapeutic target for the prevention and treatment of osteoporosis and other age-associated bone diseases
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