Cyclic Polypeptide D7 Protects BMSCs And Promotes Chondrogenesis During ONFH Via GDF 15-mediated Redox Signaling

Background:Osteonecrosis of the femoral head(ONFH)is a disabling disease that is closely associated with the clinical application of high-dose glucocorticoids.Elevated oxidative stress contributes to pathophysiological changes in ONFH.The lack of effective treatments before surgical intervention highlights the importance of finding novel therapeutics.Our previous studies demonstrated that D7,a cyclic polypeptide,enhances the adhesion,expansion,and proliferation of bone marrow mesenchymal stem cells(BMSCs).ObjectiveUsing rat bone marrow mesenchymal stem cells to study the protective effect of D7 in the process of avascular necrosis of the femoral head,and to study its molecular mechanism.Methods1.Use GEO database and femoral head tissue of patients with femoral head necrosis to analyze the difference in gene expression.2.D7 is applied to the treatment of an in vitro model of avascular necrosis of the femoral head induced by Dexamethasone(DEX)to study its therapeutic effect and molecular mechanism.ResultsWe found negative correlations among oxidative stress marker expression,growth differentiation factor 15(GDF15)levels,and ONFH.Furthermore,we demonstrated that DEX inhibited the proliferation and induced apoptosis of BMSCs by suppressing GDF 15/AKT/mammalian target of rapamycin(mTOR)signaling.D7 alleviated DEXinduced BMSCs injury and restored the chondrogenic function of BMSCs by activating GDF 15/AKT/mTOR signaling.In addition,DEX-induced excessive reactive oxygen species(ROS)generation was an upstream trigger of GDF15-mediated signaling,and D7 ameliorated this DEX-induced redox imbalance by restoring the expression of antioxidants,including superoxide dismutase(SOD)1,SOD2,and catalase,via regulation of GDF15 expression.ConclusionIn conclusion,our findings revealed the potential therapeutic effects of D7 in SONFH and showed that this protective function may be mediated via inhibition of DEXinduced ROS and activation of GDF15/AKT/mTOR signaling,thereby providing insights into the potential applications of D7 in SONFH treatment.