Curcumin controls the senescence of adipose-derived mesenchymal stem cells via the FoxO3/autophagy signaling pathway to enhance joint homeostasis for osteoarthritis therapy.

backgroundOsteoarthritis (OA) is a common chronic and degenerative disease, the pathophysiological features of which involve the whole joint. In recent years, adipose tissue-derived mesenchymal stem cells (ADSCs) have attracted much attention in the field of regenerative medicine. Nonetheless, with aging in vivo or exogenous stress in vitro, mesenchymal stem cells undergo cellular senescence, resulting in limited therapeutic efficacy. Curcumin is a natural polyphenolic compound that has antioxidative, anti-inflammatory and antiapoptotic properties. We aimed to investigate the function and molecular mechanisms of the effects of curcumin on ADSC senescence and to explore the therapeutic efficacy of curcumin-pretreated ADSCs in OA management.

methodsMouse primary ADSCs were identified using immunofluorescence staining and multilineage differentiation. Cell counting kit-8 (CCK-8) assays, reactive oxygen species (ROS) level measurements, β-galactosidase staining, Western blotting, immunofluorescence staining, and transmission electron microscopy (TEM) were performed to explore the function of curcumin in ADSCs. Bioinformatics analysis, chromatin immunoprecipitation (ChIP), small interfering RNA (siRNA), and real-time quantitative PCR (RT‒qPCR) were performed to evaluate whether FoxO3 directly regulates Becn1. In vivo, adult C57BL/6 male mice were subjected to destabilization of the medial meniscus (DMM) to establish an OA model. Histological staining with HE and Safranin O and fast green, Osteoarthritis Research Society International (OARSI) and synovitis score evaluation, histochemical staining, and microcomputed tomography (µCT) analysis were performed to assess the effects of intra-articular injection of ADSCs on OA treatment.

resultsCurcumin inhibited ROS production and mitigated ADSC senescence. Furthermore, curcumin promoted autophagy and subsequent alleviation of cell senescence via a FoxO3-dependent pathway, and FoxO3 directly regulated the autophagy-related gene Becn1. Knockdown of FoxO3 with small interfering RNA (siRNA) impaired autophagy and restored cell senescence in ADSCs. In vivo, ADSC pretreatment with curcumin optimized the therapeutic effects on cartilage degeneration and matrix metabolism, synovial inflammation and subchondral bone deterioration, thereby improving joint homeostasis and enhancing the effects of OA treatment.

conclusionsCurcumin controls ADSC senescence via the FoxO3-mediated signaling pathway, and FoxO3 directly regulates Becnl to induce autophagy. Intra-articular injection of curcumin-pretreated ADSCs enhances joint homeostasis for OA treatment. This study provides evidence for the potential clinical application of curcumin-pretreated ADSCs in enhancing the therapeutic effects of OA treatment.