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

作　　者：Qingxian Li Fan Zhang Yongguo Dai Liang Liu Liaobin Chen Hui Wang 

机构地区：[1]Department of Orthopedic Surgery,Zhongnan Hospital of Wuhan University,Wuhan 430071,China [2]Joint Disease Research Center of Wuhan University,Division of Joint Surgery and Sports Medicine,Wuhan 430071,China [3]Department of Pharmacology,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,China [4]Hubei Provincial Key Laboratory of Developmentally Originated Disease,Wuhan 430071,China

出　　处：《Science China(Life Sciences)》2024年第11期2382-2397,共16页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2020YFA0803900);the National Natural Science Foundation of China(81972036,U22A20362,82030111);Hubei Province’s Outstanding Medical Academic Leader Program(2019);China Postdoctoral Science Foundation(2023M742931).

摘　　要：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.

关 键 词：cartilage development glutamine metabolism mitochondrial biogenesis prenatal prednisone exposure fetal-originated osteoarthritis 

分 类 号：R684.3[医药卫生—骨科学]