Activation of the PGC-1α-mediated mitochondrial glutamine metabolism pathway attenuates female offspring osteoarthritis induced by prenatal excessive prednisone

Osteoarthritis is a chronic,age-related joint disease.Previous studies have shown that osteoarthritis develops during intrauterine development.Prednisone is frequently used to treat pregnancies complicated by autoimmune diseases.However,limited research has been conducted on the enduring effects of prednisone use during pregnancy on the offspring.In this study,we investigated the effect of excessive prednisone exposure on cartilage development and susceptibility to osteoarthritis in the offspring.We found that prenatal prednisone exposure(PPE)impaired cartilage extracellular matrix(ECM)synthesis,resulting in poor cartilage pathology in female offspring during the adult period,which was further exacerbated after long-distance running stimulation.Additionally,PPE suppressed cartilage development during the intrauterine period.Tracing back to the intrauterine period,we found that Pred,rather than prednisone,decreased glutamine metabolic flux,which resulted in increased oxidative stress,and decreased histone acetylation,and expression of cartilage phenotypic genes.Further,PGC-1α-mediated mitochondrial biogenesis,while PPE caused hypermethylation in the promoter region of PGC-1αand decreased its expression in fetal cartilage by activating the glucocorticoid receptor,resulting in a reduction of glutamine flux controlled by mitochondrial biogenesis.Additionally,overexpression of PGC-1α(either pharmacological or through lentiviral transfection)reversed PPEand Pred-induced cartilage ECM synthesis impairment.In summary,this study demonstrated that PPE causes chondrodysplasia in female offspring and increases their susceptibility to postnatal osteoarthritis.Hence,targeting PGC-1αearly on could be a potential intervention strategy for PPE-induced osteoarthritis susceptibility.