通过下丘脑下降通路抑制交感神经张力可促进糖皮质激素诱发的内皮损伤和股骨头坏死

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Wenkai Shao, Bo Wang, Ping Wang, Shuo Zhang, Song Gong, Xiaodong Guo, Deyu Duan, Zengwu Shao, Weijian Liu, Lei He, Fei Gao, Xiao Lv, Yong Feng
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引用次数: 0

摘要

股骨头骨坏死(ONFH)是糖皮质激素(GC)治疗的常见并发症。最新研究表明,交感神经调节骨稳态,而 GCs 可降低交感神经张力。在这里,我们发现交感神经张力的急剧下降与 GC 诱导的 ONFH 的发病机制密切相关。GCs 可激活下丘脑室旁核(PVN)神经元上的糖皮质激素受体(GR),但会阻碍矿质皮质激素受体(MR)的激活。这就破坏了皮质类固醇受体(GR/MR)的平衡,进而减少了下丘脑室旁核的交感神经外流。在每天接受甲基强的松龙(MPS)治疗 3 天的成年雄性小鼠中,血管内皮细胞会迅速对交感神经张力的抑制做出反应,引发内皮细胞凋亡。重要的是,PVN 中的 GR 抑制剂(RU486)可促进 MR 的活化并重新平衡 GR 和 MR 的比例,从而有效促进交感神经的外流,这表现在 PVN 和交感神经节后神经元中酪氨酸羟化酶的表达增加,以及 MPS 治疗小鼠股骨头血清和骨髓中去甲肾上腺素水平的增加。重新平衡皮质类固醇受体可减轻 GC 诱导的内皮损伤和 ONFH,促进股骨头的血管生成和骨生成,而 6-OHDA 化学交感神经切除术或肾上腺素能受体-β2(Adrb2)基因敲除则可消除这些影响。此外,激活体内 Adrb2 信号足以挽救 GC 诱导的 ONFH 表型。从机理上讲,去甲肾上腺素通过Adrb2-环磷酸腺苷反应元件结合蛋白(CREB)信号传导增加了关键糖酵解基因6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3(PFKFB3)的表达。在经 MPS 处理的 Adrb2 基因敲除小鼠中,内皮特异性过表达 PFKFB3 可减轻内皮损伤并防止严重骨坏死。因此,GC 可通过下丘脑下降通路抑制交感神经张力,而交感神经张力又是 GC 诱导 ONFH 的介质。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head

Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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