Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head
Abstract 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 asso...
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Nature Publishing Group
2024-11-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00371-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wenkai Shao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9e7007b7316843c9b5b7dfed9e4e156c |
| institution | DOAJ |
| issn | 2095-6231 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
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| series | Bone Research |
| spelling | doaj-art-9e7007b7316843c9b5b7dfed9e4e156c2025-08-20T02:50:03ZengNature Publishing GroupBone Research2095-62312024-11-0112112210.1038/s41413-024-00371-3Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral headWenkai Shao0Bo Wang1Ping Wang2Shuo Zhang3Song Gong4Xiaodong Guo5Deyu Duan6Zengwu Shao7Weijian Liu8Lei He9Fei Gao10Xiao Lv11Yong Feng12Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Rehabilitation, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41413-024-00371-3 |
| spellingShingle | 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 Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head Bone Research |
| title | Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head |
| title_full | Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head |
| title_fullStr | Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head |
| title_full_unstemmed | Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head |
| title_short | Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head |
| title_sort | inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid induced endothelial impairment and osteonecrosis of the femoral head |
| url | https://doi.org/10.1038/s41413-024-00371-3 |
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