骨源性因子ucOCN在运动抗抑郁中的作用机制

doi:10.3724/SP.J.1042.2022.00375

摘要/Abstract

摘要：

羧化不全骨钙素(ucOCN)是骨中成骨细胞分泌的特异性蛋白, 因其在调控神经发育、神经可塑性等中的重要角色而受到神经科学领域关注。“骨-脑”串联“对话”是骨内分泌-神经介导的应答系统, ucOCN透过血脑屏障后介导单胺类神经递质、神经内分泌、神经免疫、神经再生及基因表达等机制, 进而作用于海马CA3区、扣带回等脑区功能发挥来调节抑郁发生及改善。而ucOCN作为骨源性力学刺激敏感基因, 运动上调其表达后进入血液循环, 通过介导5-HT/GABA分泌、HPA轴功能、炎症反应、神经营养因子(BDNF等)表达或信号途径(如GSK3β/β-catenin、TLR4/miR-223/NLRP3等)激活等来实现“骨串联脑”, 发挥运动抗抑郁作用。通过对骨源性因子ucOCN介导脑区功能变化从而实现运动抗抑郁的作用机制进行探讨、梳理, 一方面有助于更深入了解骨内分泌功能, 另一方面为抑郁发生、改善和运动抗抑郁研究提供新的理论基础和研究思路。

关键词: 羧化不全骨钙素, 骨, 脑, 运动, 抑郁症

Abstract:

Depression is a major problem in the modern society. The pathogenesis of depression is a research hotspot in the field of neuroscience. The proved mechanisms of depression include monoamine neurotransmitter hypothesis, gene-environment interaction, neurogenesis, neuroplasticity, immune activation and suppression, etc. With the deepening of research, the roles of "brain-gut interaction", "muscle-brain crosstalk", and adipocytokines in the sports antidepressant field has been discovered. As an endocrine organ, the role of bone tissue in anti-depressive exercise remains to be revealed. Based on this, this research innovatively explores the biological effects and mechanisms of uncarboxylated osteocalcin (ucOCN) in exercise anti-depression from the perspective of “bone-brain crosstalk”, and further reveals the relationship between bone endocrine activity and the molecular regulation of sports antidepressant. ucOCN is a specific non-collagen protein secreted by osteoblasts (OB). After entering the blood, it acts on the hippocampus, cingulate gyrus and other brain tissues, and triggers a cascade reaction through targeting cell membrane receptors to regulate neurodevelopment, neuroplasticity and bone endocrine-nerve response system. Exercise promotes the secretion of ucOCN and has a significant antidepressant effect, but there are few studies focusing on the molecular mechanism. Based on integrated biological theory and bone endocrine function, through analysis of current research, we found several mechanisms by which ucOCN mediating exercise antidepressant. Firstly, ucOCN regulates neurotransmitters expression: exercise induces high expression of ucOCN which inhibits γ-amino groups butyric acid (GABA) expression to improve depression-like behavior. Secondly, ucOCN regulates neuroendocrine secretion: ucOCN activates the HPA axis to promote adrenocorticotropic hormone (ACTH), mineralocorticoid, cortisol and other secretions to improve depression-like behavior. In addition, ucOCN also activates G protein-coupled receptors 158 (Gpr158)/brain-derived neurotrophic factor (BDNF) pathway to promote neurotransmitter secretion and further regulate depression occurring. Thirdly, ucOCN regulates neuroimmunity: ucOCN activates the ERK and STAT pathways and down-regulates the expression of IL-6 and IL-8 in the hippocampus, and then through malondialdehyde (MDA)/super up-regulation of superoxide dismutase (SOD)/nuclear factor erythroid-derived 2-like 2(Nrf2)/heme oxygenase 1(HO1) pathway to increase expression of VGF and BDNF, which further improve depression-like behaviors. Taken together, these results provide a solid theoretical basis for the mechanism of ucOCN in sports anti-depression. We also provides new research directions and ideas for sports anti-depression, and provide a new perspective for enriching the biological mechanism network of sports brain.

Key words: undercarboxylated osteocalcin, bone, brain, exercise, depression

中图分类号:

B845

陈祥和, 李文秀, 刘波, 殷荣宾. (2022). 骨源性因子ucOCN在运动抗抑郁中的作用机制. 心理科学进展 , 30(2), 375-388.

CHEN XiangHe, LI WenXiu, LIU Bo, YIN RongBin. (2022). The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise. Advances in Psychological Science, 30(2), 375-388.

图/表 2

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发生机制	介导/调控的分子机制及基因、蛋白活动
调节神经递质	a. 5-HTTLPR短等位基因在慢性应激下易患抑郁; b. ucOCN下调NMDA表达, AMPAR表达↑, 谷氨酸、BDNF↑, GABA↓, 快速抗抑郁; c. Gpr158影响MF-CA1区神经远树突结构和功能调控抑郁发生;
调节神经内分泌	a. 敲除ucOCN后, GC↑, 引发抑郁样行为; b. 血清ucOCN↓, 激活HPA轴, ACTH和皮质醇↑, 抑制海马对HPA轴的负反馈调节; c. 敲除ucOCN后, GPRC6A失活, 胰岛素↓, 激活海马区炎症反应和IR, Ezrin表达↓。
介导神经免疫机制	a. 应激状态下, CRH↑, 交感神经系统和HPA轴激活, 抑制正常免疫反应; b. NF-κB激活C3参与抑郁发生; c. NF-κB激活后, C3释放↑, 作用于神经细胞上的C3受体; NF-κB/C3/C3aR途径参与神经内钙电流调节, 突触后电流↑, 并受AMPAR调节影响抑郁发生; d. 缺失ucOCN, ATP不能正常合成, IP3Rs2和囊泡胶质细胞诱导ATP缺陷, 抑郁小鼠模型内测P2X2受体介导ATP抗抑郁; e. ucOCN作用于炎症AKT/mTOR/NF-κB途径和星型胶质细胞调控抑郁发生; f. ucOCN直接作用于IL-6、IL-8、IL-1β表达, 影响HPA轴调控抑郁发生。 g. ucOCN上调PVT1表达, 抑制TNF-α、IL-1β、IL-6作用于PKC后上调BDNF, TUNEL数量↓, 激活AKT/ mTOR途径并调节Aβ相关蛋白表达, 改善抑郁样行为; h. 体外实验, ucOCN通过AKT/mTOR途径保护Aβ-42损伤PC12细胞实现上述效果。
调节神经再生	a. 骨中Runx2↓, ucOCN↓, 认知功能损; b. ucOCN敲除后, 神经元数量减少, 再生能力下降, 抑郁易发生。

发生机制	介导/调控的分子机制及基因、蛋白活动
调节神经递质	a. 5-HTTLPR短等位基因在慢性应激下易患抑郁; b. ucOCN下调NMDA表达, AMPAR表达↑, 谷氨酸、BDNF↑, GABA↓, 快速抗抑郁; c. Gpr158影响MF-CA1区神经远树突结构和功能调控抑郁发生;
调节神经内分泌	a. 敲除ucOCN后, GC↑, 引发抑郁样行为; b. 血清ucOCN↓, 激活HPA轴, ACTH和皮质醇↑, 抑制海马对HPA轴的负反馈调节; c. 敲除ucOCN后, GPRC6A失活, 胰岛素↓, 激活海马区炎症反应和IR, Ezrin表达↓。
介导神经免疫机制	a. 应激状态下, CRH↑, 交感神经系统和HPA轴激活, 抑制正常免疫反应; b. NF-κB激活C3参与抑郁发生; c. NF-κB激活后, C3释放↑, 作用于神经细胞上的C3受体; NF-κB/C3/C3aR途径参与神经内钙电流调节, 突触后电流↑, 并受AMPAR调节影响抑郁发生; d. 缺失ucOCN, ATP不能正常合成, IP3Rs2和囊泡胶质细胞诱导ATP缺陷, 抑郁小鼠模型内测P2X2受体介导ATP抗抑郁; e. ucOCN作用于炎症AKT/mTOR/NF-κB途径和星型胶质细胞调控抑郁发生; f. ucOCN直接作用于IL-6、IL-8、IL-1β表达, 影响HPA轴调控抑郁发生。 g. ucOCN上调PVT1表达, 抑制TNF-α、IL-1β、IL-6作用于PKC后上调BDNF, TUNEL数量↓, 激活AKT/ mTOR途径并调节Aβ相关蛋白表达, 改善抑郁样行为; h. 体外实验, ucOCN通过AKT/mTOR途径保护Aβ-42损伤PC12细胞实现上述效果。
调节神经再生	a. 骨中Runx2↓, ucOCN↓, 认知功能损; b. ucOCN敲除后, 神经元数量减少, 再生能力下降, 抑郁易发生。