A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.
A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.
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DOI：
10.1016/j.stem.2022.02.008
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发表时间：
2022-04-07
期刊：
影响因子：
23.9
通讯作者：
Mendez-Ferrer, Simon
中科院分区：
文献类型：
--
作者：
Gadomski, Stephen;Fielding, Claire;Garcia-Garcia, Andres;Korn, Claudia;Kapeni, Chrysa;Ashraf, Sadaf;Villadiego, Javier;Del Toro, Raquel;Domingues, Olivia;Skepper, Jeremy N.;Michel, Tatiana;Zimmer, Jacques;Sendtner, Regine;Dillon, Scott;Poole, Kenneth E. S.;Holdsworth, Gill;Sendtner, Michael;Toledo-Aral, Juan J.;De Bari, Cosimo;McCaskie, Andrew W.;Robey, Pamela G.;Mendez-Ferrer, Simon
自主神经系统是体内平衡过程和应激反应的主要调节器。交感去甲肾上腺素能神经纤维减少骨量，但胆碱能信号在骨中的作用仍然很大程度上未知。在这里，我们描述了出生后早期，交感神经纤维的一个子集经历了白细胞介素-6（IL-6）诱导的胆碱能开关接触骨。交感胆碱能纤维和骨包埋的骨细胞之间通过GDNF-家族受体-α2（GFRα2）及其配体neurturin（NRTN）介导的神经营养依赖性建立，其存活和连接需要胆碱能神经支配。骨衬骨祖细胞在骨髓（BM）中放大和传播胆碱能信号。适度运动增强骨小梁部分通过IL-6依赖性交感胆碱能神经纤维扩张。因此，胆碱能骨骼神经支配的丧失降低了骨细胞的存活和功能，导致骨质减少和骨骼对适度运动的适应性受损。这些结果揭示了胆碱能神经-骨细胞界面通过骨合成代谢作用调节骨骼发生和骨骼周转。IL-6诱导生后骨接触交感神经元的胆碱能开关Neurturin-GFRα2途径维持胆碱能神经-骨细胞偶联和存活骨衬里骨祖细胞放大骨和骨髓中的胆碱能信号IL-6诱导的胆碱能信号在中度运动期间具有骨合成代谢作用Gadomski et al.描述了神经-骨细胞界面，交感胆碱能神经元通过GFRα2神经营养通路支持骨包埋的骨细胞。在发育过程中，这些交感神经元经历了从肾上腺素能到胆碱能的神经递质转换，这是一个由白细胞介素-6诱导的过程，并通过身体活动动态增强以增加骨量。
The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects. IL-6 induces a cholinergic switch of sympathetic neurons contacting bone postnatally Neurturin-GFRα2 pathway maintains cholinergic neuro-osteocyte coupling and survival Bone-lining osteoprogenitors amplify cholinergic signaling in bone and bone marrow IL-6-induced cholinergic signaling has a bone-anabolic effect during moderate exercise Gadomski et al. describe a neuro-osteocyte interface whereby sympathetic cholinergic neurons support bone-embedded osteocytes through the GFRα2 neurotrophic pathway. Developmentally, these sympathetic neurons undergo a neurotransmitter switch from adrenergic to cholinergic—a process that is induced by interleukin-6 and is dynamically enhanced by physical activity to increase bone mass.
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影响因子：
8.8
作者：
Gadomski S;Singh SK;Singh S;Sarkar T;Klarmann KD;Berenschot M;Seaman S;Jakubison B;Gudmundsson KO;Lockett S;Keller JR
通讯作者：
Keller JR
影响因子：
16.6
作者：
Fielding C;García-García A;Korn C;Gadomski S;Fang Z;Reguera JL;Pérez-Simón JA;Göttgens B;Méndez-Ferrer S
通讯作者：
Méndez-Ferrer S
DOI：
10.1152/ajpendo.2001.280.2.e378
发表时间：
2001-02-01
影响因子：
5.1
作者：
Benthem, L;Mundinger, TO;Taborsky, GJ
通讯作者：
Taborsky, GJ
影响因子：
2.5
作者：
Berman, Alycia G.;Hinton, Madicyn J.;Wallace, Joseph M.
通讯作者：
Wallace, Joseph M.
影响因子：
20.3
作者：
Garcia-Garcia, Andres;Korn, Claudia;Mendez-Ferrer, Simon
通讯作者：
Mendez-Ferrer, Simon