Qingxian Li, Fan Zhang, Yongguo Dai, Liang Liu, Liaobin Chen, Hui Wang
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引用次数: 0
Abstract
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-1α and 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 PPE- and 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-1α early on could be a potential intervention strategy for PPE-induced osteoarthritis susceptibility.
骨关节炎是一种与年龄有关的慢性关节疾病。以往的研究表明,骨关节炎是在宫内发育过程中形成的。泼尼松常用于治疗妊娠合并自身免疫性疾病。然而,关于孕期使用泼尼松对后代的持久影响的研究却很有限。在这项研究中,我们调查了过量泼尼松暴露对后代软骨发育和骨关节炎易感性的影响。我们发现,产前泼尼松暴露(PPE)会损害软骨细胞外基质(ECM)的合成,从而导致雌性后代成年后软骨病理状况不佳,而长跑刺激会进一步加剧这种状况。此外,PPE 还会抑制宫内软骨的发育。追溯到宫内期,我们发现Pred而不是泼尼松降低了谷氨酰胺代谢通量,从而导致氧化应激增加、组蛋白乙酰化减少以及软骨表型基因的表达。此外,PGC-1α 介导线粒体生物生成,而 PPE 通过激活糖皮质激素受体,导致 PGC-1α 启动子区域甲基化过度,并降低其在胎儿软骨中的表达,从而导致线粒体生物生成控制的谷氨酰胺通量减少。此外,过表达 PGC-1α(药理或通过慢病毒转染)可逆转 PPE 和 Pred 诱导的软骨 ECM 合成障碍。总之,本研究证明,PPE 会导致雌性后代软骨发育不良,并增加其对出生后骨关节炎的易感性。因此,早期靶向 PGC-1α 可能是干预 PPE 诱导的骨关节炎易感性的一种潜在策略。
期刊介绍:
Science China Life Sciences is a scholarly journal co-sponsored by the Chinese Academy of Sciences and the National Natural Science Foundation of China, and it is published by Science China Press. The journal is dedicated to publishing high-quality, original research findings in both basic and applied life science research.