PDF(Pubmed)
Abstract：
Chondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0-20 and underwent long-distance running during postnatal weeks (PWs) 24-28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long-distance running, the PPE group exhibited more typical osteoarthritis-like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48-linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFβ pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra-articular injection of offspring with AAV-circGtdc1 ameliorated PPE-induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1-Srsf1-Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE-induced chondrodysplasia.
摘要：
软骨发育不良与低出生体重和成年期骨关节炎易感性增加密切相关。产前泼尼松暴露（PPE）可导致低出生体重；然而，其对后代软骨发育的影响仍有待探索。在这里，大鼠在妊娠天数(GDs)0-20时胃内给予临床剂量的泼尼松,并在产后周(PWs)24-28时进行长跑。在GD20、PW12和PW28上测定膝关节软骨的质量和相关指数变化。进行体外实验以阐明机制。PPE减少软骨增殖和基质合成，导致后代软骨发育不良。长跑之后,PPE组表现出更典型的骨关节炎样变化.分子分析显示，PPE引起软骨circRNomics失衡，其中circtdc1下降最明显，并在出生后持续存在。机械上,泼尼松龙通过K48连接的多泛素化减少circGtdc1的表达并与Srsf1结合以促进Srsf1的降解。这进一步抑制了EDA/B+Fn1的形成和PI3K/AKT和TGFβ通路的活化,减少软骨细胞增殖和基质合成。最后,子代关节内注射AAV-circGtdc1改善PPE诱导的软骨发育不良，但是Srsf1敲除可以逆转这种效果。总之,这项研究证实，PPE通过改变circGtdc1-Srsf1-Fn1轴导致软骨发育不良和骨关节炎的易感性；在体内，circGtdc1的过表达可以代表改善PPE诱导的软骨发育不良的有效干预目标。
