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.

股骨头骨坏死 （ONFH） 是糖皮质激素 （GC） 治疗的常见并发症。最近的进展表明，交感神经调节骨稳态，而 GCs 降低交感神经张力。在这里，我们表明交感神经张力的急剧降低与 GC 诱导的 ONFH 的发病机制密切相关。GC 激活糖皮质激素受体 （GR），但阻碍下丘脑室旁核 （PVN） 神经元上盐皮质激素受体 （MR） 的激活。这会破坏皮质类固醇受体 （GR/MR） 的平衡，从而减少 PVN 中的交感神经流出。血管内皮细胞通过每天用甲泼尼龙 （MPS） 处理 3 天的成年雄性小鼠的内皮细胞凋亡来迅速反应交感神经张力的抑制，我们发现 MPS 处理的 ONFH 小鼠的股骨头中的 H 型血管显着减少。重要的是，在 PVN 中用 GR 抑制剂 （RU486） 治疗可促进 MR 的激活并重新平衡 GR 和 MR 的比率，从而有效促进交感神经流出，如 PVN 和交感神经节后神经元中酪氨酸羟化酶表达的增加以及 MPS 处理小鼠股骨头血清和骨髓中去甲肾上腺素水平的增加所示。再平衡皮质类固醇受体可减轻 GC 诱导的内皮损伤和 ONFH，并促进血管生成与股骨头成骨结合，而这些影响则被 6-OHDA 或肾上腺素能受体-β （Adrb2） 敲除的化学交感神经切除术消除。此外，在体内激活 Adrb2 信号传导足以挽救 GC 诱导的 ONFH 表型。 从机制上讲，去甲肾上腺素通过 Adrb2-环状 AMP 反应元件结合蛋白 （CREB） 信号传导增加关键糖酵解基因 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 （PFKFB3） 的表达。PFKFB3 的内皮特异性过表达可减轻 MPS 处理的 Adrb2 敲除小鼠的内皮损伤并防止严重的骨坏死。因此，GC 通过下丘脑下行通路抑制交感神经张力，这反过来又充当 GC 诱导的 ONFH 的介质。