Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, China.
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China; Joint Disease Research Center of Wuhan University, Wuhan 430071, China.
Pharmacol Res. 2022 Jan;175:105990. doi: 10.1016/j.phrs.2021.105990. Epub 2021 Nov 19.
Epidemiological investigations have shown that individuals treated with dexamethasone during pregnancy have an increased risk of osteoporosis after birth. Our studies reported that peak bone mass was decreased in the prenatal dexamethasone exposure (PDE) offspring before chronic stress, while further decrease was observed after chronic stress. Simultaneously, increase of bone local active corticosterone was observed in the PDE offspring, while further increase was also observed after chronic stress. Moreover, the histone H3 lysine 9 acetylation (H3K9ac) level of 11-beta hydroxysteroid dehydrogenase 2 (11β-HSD2) and its expression in bone tissue of PDE offspring rats remained lower than the control before and after birth. Injection of 11β-HSD2 overexpression lentivirus into the bone marrow cavity could partially alleviate the accumulation of bone local active corticosterone and bone loss induced by PDE. In vitro, dexamethasone inhibited the expression of 11β-HSD2 and aggravated the inhibitory effect of corticosterone on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Overexpression of 11β-HSD2 partially alleviated the inhibitory effect of corticosterone. Moreover, dexamethasone promoted the nuclear translocation of glucocorticoid receptor (GR), which resulted in the stimulation of 11β-HSD2 expression due to the binding of GR to the 11β-HSD2 promoter region directly, as well as increasing H3K9ac level in the 11β-HSD2 promoter region by recruiting histone deacetylase 11 (HDAC11). Our results indicated that low expression of 11β-HSD2 in bone tissue is an important mediator for the high susceptibility to osteoporosis in PDE adult offspring.
流行病学研究表明，孕期接受地塞米松治疗的个体在出生后发生骨质疏松症的风险增加。我们的研究报告称，在慢性应激前，产前地塞米松暴露（PDE）后代的峰值骨量减少，而在慢性应激后进一步减少。同时，在 PDE 后代中观察到骨局部活性皮质酮增加，而在慢性应激后进一步增加。此外，在 PDE 后代大鼠的骨组织中，11-β-羟类固醇脱氢酶 2（11β-HSD2）的组蛋白 H3 赖氨酸 9 乙酰化（H3K9ac）水平及其表达在出生前后均低于对照组。向骨髓腔注射 11β-HSD2 过表达慢病毒可部分缓解 PDE 引起的骨局部活性皮质酮积累和骨丢失。在体外，地塞米松抑制 11β-HSD2 的表达，并加重皮质酮对骨髓间充质干细胞（BMSCs）成骨分化的抑制作用。11β-HSD2 的过表达部分缓解了皮质酮的抑制作用。此外，地塞米松促进了糖皮质激素受体（GR）的核转位，导致 11β-HSD2 表达的刺激，这是由于 GR 直接结合到 11β-HSD2 启动子区域，以及通过募集组蛋白去乙酰化酶 11（HDAC11）增加 11β-HSD2 启动子区域的 H3K9ac 水平所致。我们的研究结果表明，骨组织中 11β-HSD2 的低表达是 PDE 成年后代骨质疏松症高易感性的重要介导物。
