Abstract：
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.
摘要：
我们先前的研究报道，产前咖啡因暴露（PCE）可以诱发软骨发育不良并增加后代大鼠对骨关节炎的易感性。然而,潜在的机制和启动因素仍然未知。本研究旨在探讨糖皮质激素代谢酶11β-HSD2参与PCE诱导的骨关节炎的易感性,并进一步探讨其可能的机制和启动因素。首先,我们发现PCE降低了雄性成年后代大鼠的软骨基质合成（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启动子处的H3K9ac和H3K27ac水平持续降低以及从胎儿到成年的软骨中的表达有关。11β-HSD2，聚集蛋白聚糖和Col2a1在胎儿软骨细胞中的表达均被皮质酮降低，而11β-HSD2的过表达可以部分缓解皮质酮体外诱导的基质合成减少。此外，被糖皮质激素激活的糖皮质激素受体（GR）直接结合到11β-HSD2的启动子区以抑制其表达。同时,激活的GR通过募集HDAC4和促进GR-HDAC4蛋白相互作用来抑制11β-HSD2表达，从而降低了11β-HSD2的H3K9ac和H3K27ac水平。此外，咖啡因可以通过抑制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作用。总之,从胎儿到成年期，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对骨关节炎的易感性增加。子宫内的这种表观遗传编程变化是由糖皮质激素与咖啡因的协同作用诱导的。
