Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Ecotoxicol Environ Saf. 2022 Jul 1;239:113624. doi: 10.1016/j.ecoenv.2022.113624. Epub 2022 May 16.
Our previous study reported that prenatal caffeine exposure (PCE) could induce chondrodysplasia and increase the susceptibility to osteoarthritis in offspring rats. However, the potential mechanisms and initiating factors remain unknown. This study aims to investigate whether 11β-HSD2, a glucocorticoid-metabolizing enzyme, is involved in the susceptibility of osteoarthritis induced by PCE and to further explore its potential mechanisms and initiating factors. Firstly, we found that PCE reduced cartilage matrix synthesis (aggrecan/Col2a1 expression) in male adult offspring rats and exhibited an osteoarthritis phenotype following chronic stress, which was associated with persistently reduced H3K9ac and H3K27ac levels at the promoter of 11β-HSD2 as well as its expression in the cartilage from fetus to adulthood. The expression of 11β-HSD2, aggrecan and Col2a1 were all decreased by corticosterone in the fetal chondrocytes, while overexpression of 11β-HSD2 could partially alleviate the decrease of matrix synthesis induced by corticosterone in vitro. Furthermore, the glucocorticoid receptor (GR) activated by glucocorticoids directly bonded to the promoter region of 11β-HSD2 to inhibit its expression. Meanwhile, the activated GR reduced the H3K9ac and H3K27ac levels of 11β-HSD2 by recruiting HDAC4 and promoting GR-HDAC4 protein interaction to inhibit the 11β-HSD2 expression. Moreover, caffeine could reduce the expression of 11β-HSD2 by inhibiting the cAMP/PKA signaling pathway but without reducing the H3K9ac and H3K27ac levels of 11β-HSD2, thereby synergistically enhancing the corticosterone effect. In conclusion, the persistently reduced H3K9ac and H3K27ac levels of 11β-HSD2 from fetus to adulthood mediated the inhibition of cartilage matrix synthesis and the increased susceptibility to osteoarthritis. This epigenetic programming change in utero was induced by glucocorticoids with synergistic effect of caffeine.
我们之前的研究报告表明，产前咖啡因暴露（PCE）可诱导软骨发育不良，并增加后代大鼠患骨关节炎的易感性。然而，潜在的机制和启动因素尚不清楚。本研究旨在探讨 11β-HSD2（一种糖皮质激素代谢酶）是否参与 PCE 诱导的骨关节炎易感性，并进一步探讨其潜在机制和启动因素。首先，我们发现 PCE 降低了雄性成年后代大鼠软骨基质合成（聚集蛋白聚糖/Col2a1 表达），并在慢性应激后表现出骨关节炎表型，这与 11β-HSD2 启动子处 H3K9ac 和 H3K27ac 水平的持续降低以及其在胎儿到成年期软骨中的表达有关。皮质酮在胎儿软骨细胞中降低了 11β-HSD2、聚集蛋白聚糖和 Col2a1 的表达，而过表达 11β-HSD2 可部分缓解皮质酮体外诱导的基质合成减少。此外，糖皮质激素激活的糖皮质激素受体（GR）直接结合到 11β-HSD2 的启动子区域，抑制其表达。同时，激活的 GR 通过募集 HDAC4 并促进 GR-HDAC4 蛋白相互作用来降低 11β-HSD2 的 H3K9ac 和 H3K27ac 水平，从而抑制 11β-HSD2 的表达。此外，咖啡因可通过抑制 cAMP/PKA 信号通路降低 11β-HSD2 的表达，但不降低 11β-HSD2 的 H3K9ac 和 H3K27ac 水平，从而协同增强皮质酮的作用。总之，从胎儿到成年，11β-HSD2 的 H3K9ac 和 H3K27ac 水平持续降低介导了软骨基质合成的抑制和骨关节炎易感性的增加。这种宫内糖皮质激素协同咖啡因作用诱导的表观遗传编程变化。
