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骨源活性物质及细胞与神经精神疾病的关系

来源:原创论文网 添加时间:2021-02-22

  摘    要: 骨是机体的主要支持结构,也是参与机体运动和钙磷代谢的主要器官。骨也是一种潜在的新型内分泌器官,其通过骨细胞和骨髓分泌的多种生物活性物质,参与心血管、消化、内分泌等多个系统的生理和病理生理过程。骨源活性物质还可直接作用于中枢神经系统,参与脑功能和个体行为的调节,骨-脑轴的双向调控也逐渐引起了神经科学研究领域的关注。本文综述了骨源活性物质和骨源细胞对个体脑功能和脑疾病的调节作用以及相关神经精神疾病的发生发展,简介了其中枢调控功能的相关机制,为基于骨-脑调控轴的神经精神疾病机制研究和防治策略的建立拓宽了思路。

  关键词: 骨; 中枢神经系统; 内分泌; 神经保护; 精神疾病;

  Abstract: Bone is not only the main supporting structure of the body, but also the main organ involved in body movement, calcium and phosphorus metabolism. Studies have shown that bone is also a potential new endocrine organ, which participates in the physiological and pathophysiological processes of cardiovascular, digestive and endocrine systems through a variety of bioactive substances secreted by bone cells and bone marrow. Bone derived active substances can also directly act on the central nervous system and participate in the regulation of brain function and individual behavior. The bidirectional regulation of bone brain axis has gradually attracted attention in the field of neuroscience. This review discussed the regulatory effects of bone derived active substances and bone derived cells on individual brain function and brain diseases, as well as the occurrence and development of related psychiatric diseases. The mechanism of central regulatory function is briefly introduced, which will broaden the thinking for the mechanism research and the establishment of prevention and treatment strategies of psychiatric diseases based on bone brain regulatory axis.

  Keyword: bone; central nervous system; endocrine; neuroprotection; psychiatric disorder;

  中枢调控功能失调是众多神经精神疾病发生的主要病理生理学基础,涉及机体多系统(下丘脑-垂体-肾上腺轴、下丘脑-垂体-性腺轴、脑-肠轴、脑-肝轴等)的稳态失衡。骨是机体重要的支持组织,其内分泌功能也逐渐引起人们的关注,脑与骨之间也可通过多种机制产生双向调控,被称为骨-脑轴或脑-骨轴。研究发现,骨能合成并分泌多种生物活性物质,如骨调节蛋白、生长因子、脂肪因子、炎症因子和心血管活性多肽等,以旁/自分泌方式调节自身和其他外周器官的发育和代谢[1]。同时,多种类型的骨源细胞与中枢功能调控和神经精神疾病发生发展关系密切。基于骨的内分泌功能,本文主要综述了骨源活性物质、骨源细胞对神经精神疾病的调控效应及其作用机制,以期为神经精神疾病的防治研究拓宽思路。
 

骨源活性物质及细胞与神经精神疾病的关系
 

  1 、骨源活性物质与神经精神疾病

  骨分泌的生物活性物质如骨钙素(osteocalcin,OCN)、脂质运载蛋白2(lipocalin 2,LCN2)、骨硬化蛋白(sclerostin,SOST)、Dickkopf相关蛋白1(Dickkopf-related protein 1,Dkk1)等,可通过外周循环以远距分泌的方式透过血脑屏障(blood brain barrier,BBB)调节机体中枢的功能与代谢(表1),同时部分类型的骨源细胞也能迁移至大脑,发挥重要的中枢调控功能(图1)[27,28,29]。

  表1 骨源活性物质的中枢调控作用
表1 骨源活性物质的中枢调控作用

  图1 骨源活性物质与骨衍生细胞
图1 骨源活性物质与骨衍生细胞

  注:Osteoblast:成骨细胞;Osteocyte:骨细胞;BMSCs:bone marrow derived mesenchymal stem cells,骨髓源间充质干细胞;BMDML:bone marrow derived microglia-like cells,骨髓源小胶质样细胞;BMM:bone marrow derived macrophages,骨髓源巨噬细胞

  1.1、 骨源活性物质与阿尔兹海默症

  阿尔兹海默病(Alzheimer's disease,AD)是一种起病隐匿的神经系统退行性疾病。成骨细胞合成并分泌的骨钙素循环水平同认知功能一样与年龄呈负相关,骨钙素循环水平增高对预防年龄相关的认知衰退具有明显的调控作用[2]。骨钙素还可穿过BBB进入中枢神经系统,与位于海马CA3区锥体神经元上的G蛋白偶联受体158结合,促使单胺类神经递质(5-羟色胺、多巴胺和去甲肾上腺素)合成增高,同时使抑制性神经递质γ-氨基丁酸(γ-aminobutyric acid,GABA)的合成降低,进而提高个体的空间学习和记忆能力[3]。

  SOST是一种主要由骨细胞合成的糖蛋白,可通过与低密度脂蛋白受体相关蛋白4/5/6(Lrp4/5/6)结合拮抗Wnt/β-catenin信号通路,导致骨吸收增加和骨骼形成减少[7,8]。在大脑中,Wnt/β-catenin信号对于神经发生、神经突触可塑性和BBB完整性至关重要[9],且与AD的病理生理相关[10]。因AD患者的BBB通透性增加,SOST可能透过BBB影响AD进展[11]。然而,由于机体内多器官参与表达SOST,骨源性SOST的药理学抑制作用是否会影响大脑中的Wnt/β-catenin信号传导并影响AD的发生发展还需进一步研究[12,13]。

  与SOST相似,由成骨细胞合成的Dkk1也是W n t信号转导的负调控因子,在骨骼中Dkk1与Lrp6结合并拮抗Wnt/β-catenin途径[17]。在大脑中Dkk1的过表达导致突触减少和神经元凋亡,为神经退行性疾病中神经元死亡的常见标志物[18]。在衰老或AD患者大脑中,Wnt信号减弱[19],Dkk1表达上调[20,21]。另一方面,Dkk1表达失调与AD脑神经元变性有关,β-淀粉样蛋白会引起p53依赖的Dkk1诱导,在Dkk1缺失的小鼠模型中发现Dkk1对年龄相关的记忆丧失具有保护作用[22]。尽管骨源性Dkk1很难被动地穿过BBB进入中枢,但内皮细胞中的主动转运系统(Dkk1受体)可能有助于Dkk1转运穿过BBB[23]。此外,由于AD中的BBB被破坏[11],可以促进Dkk1穿过BBB并加剧AD进展。除BBB途径外,Dkk1还可以通过下丘脑和脉络丛渗透到大脑中[23]。虽然未证实骨源Dkk1能对AD恢复产生直接影响,但为治疗AD提供了新思路。

  1.2 、骨源活性物质与缺血性脑卒中

  缺血性脑卒中(ischemic stroke,IS)患者血清中SOST和Dkk1的含量显着升高,但两者的血清含量变化与IS的严重度或结局无相关性[15]。SOST可以显着抑制骨形态发生蛋白2诱导的收缩性血管平滑肌细胞向成骨细胞转化并减少骨形态发生蛋白2诱导的矿化作用[16]。此外,骨源性SOST可能通过激活维生素D受体或抑制Wnt信号传导保护血管免于钙化,减少个体心脑血管疾病风险[16]。SOST和Dkk1可能透过IS后破坏BBB在中枢发挥作用,进而加速IS患者康复[14]。

  1.3、 骨源活性物质与抑郁症

  抑郁症是一种以心境持久低落为主要特征的综合征,该疾病与骨矿物质密度降低相关[30],其患者血清常伴有骨钙素代偿性增高[4]。成骨细胞分泌的骨钙素可穿过BBB进入中枢神经系统,直接与脑干、中脑和海马神经元结合,增强单胺类神经递质的产生,抑制GABA合成,降低了脑干和中脑中谷氨酸脱羧酶1的表达,增加了色氨酸羟化酶2(tryptophan hydroxylase 2,Tph2)和酪氨酸羟化酶(tyrosine hydroxylase,Th)的表达,延缓了焦虑和抑郁样行为的发生[3]。骨钙素基因敲除小鼠经侧脑室注射骨钙素后可完全逆转其焦虑和抑郁样行为,并改善其在空间学习和记忆任务中的表现[3]。母体骨钙素可在孕期穿过胎盘,阻止胚胎海马神经元凋亡和脑室增大,并通过增加胚胎纹状体多巴胺含量降低脑干、中脑、纹状体GABA水平促进海马齿状回的神经发生[2,3]。

  1.4、 骨源活性物质与帕金森氏病

  帕金森氏病(Parkinson's disease,PD)发病机制涉及黑质-纹状体多巴胺通路变性,乙酰胆碱系统功能亢进等[5]。成骨细胞分泌的骨钙素参与中枢多巴胺能神经元发育,在PD模型大鼠的脑脊液中骨钙素含量显着低于对照组,经骨钙素干预可明显改善PD大鼠的行为障碍,并减少黑质纹状体系统中酪氨酸羟化酶的损失[6]。此外,骨钙素还可抑制PD大鼠黑质中的星形胶质细胞和小胶质细胞增殖[6]。体外研究表明,骨钙素通过丝氨酸苏氨酸蛋白激酶-糖原合成激酶3β(Akt-GSK3β)信号通路明显改善了6-羟基多巴胺的神经毒性[6],提示骨钙素在PD中具有潜在的治疗用途。

  1.5 、骨源活性物质与进食障碍

  进食障碍(eating disorders,ED)与下丘脑黑色素皮质素4受体(melanocortin-4 receptor,MC4R)的激活关系密切[25]。下丘脑MC4R是由下丘脑的室旁核(paraventricular nucleus of hypothalamus,PVN)分泌的一种肽类物质,属于G蛋白偶联的跨膜神经性受体,在控制食欲、能量平衡及体重等过程中起着关键作用[26]。由成骨细胞分泌的LCN2可透过BBB在中枢发挥作用,通过与下丘脑中MC4R结合可激活机体厌食行为,该原理可用来调控进食障碍患者的异常进食行为,为治疗ED提供了新策略[24]。

  2、 骨源细胞与神经精神疾病

  骨骼成分除矿物质化的骨骼组织外还包括骨髓、骨膜、神经、血管和软骨。其中骨髓存在于骨松质腔隙和长骨骨髓腔内,由多种类型的细胞和网状结缔组织构成,其衍生细胞如BMSCs、BMDML等可同骨源活性物质一样迁移至中枢神经系统影响神经精神疾病的进展(表2)。

  2.1、 骨源细胞与阿尔兹海默症

  BMSCs具有从骨髓迁移至外周血并最终进入中枢的能力[28]。给予AD小鼠静脉注射或脑内移植BMSCs可减少其大脑神经炎性斑块(neuritic plaque,NP)的形成,促进其海马血管增殖以及大脑皮层和海马小胶质细胞活化,并挽救其认知障碍[31,32,33]。此外,BMSCs移植至AD小鼠海马脑区后可分化为胆碱乙酰化转移酶样神经元,显着改善小鼠的学习和记忆能力[32]。

  AD临床研究结果显示,BMDML可通过趋化因子依赖的方式透过BBB迁移到大脑[32],并通过分泌转化生长因子-β1(transforming growth factor-β1,TGF-β1)限制β-淀粉样蛋白(beta-amyloid protein,Aβ)的形成并促进Aβ斑块快速清除[38],进而改善AD个体的认知功能障碍[39]。

  此外,随着年龄增长,BMM向大脑的浸润逐渐增加[45],通过全身移植BMM可以减少AD个体的脑部Aβ沉积和神经炎症[46]。总之,越来越多的实验证据表明,骨髓来源的细胞可以进入中枢神经系统并抑制AD的病理进展,为AD患者提供了有希望的新治疗手段。

  2.2、 骨源细胞与缺血性脑卒中

  LCN2是mi R-138-5p的靶基因并在IS发病期间高度表达[34]。BMSCs衍生的含有mi R-138-5p的外泌体可被星形胶质细胞内吞,通过负调控LCN2表达促进星形胶质细胞增殖,同时抑制IS后的星形胶质细胞凋亡和炎症反应,减轻IS小鼠神经元损伤并为脑缺血和再灌注损伤提供保护[34]。

  2.3 、骨源细胞与抑郁症

  Mi R-26a参与了机体应激反应调节和神经精神疾病的发生发展,在抑郁症患者血液中呈现低表达状态,服用抗抑郁药物依他普仑后其表达显着上调[35]。在经注射皮质酮建立的抑郁症模型大鼠中,脑室注射BMSCs衍生的外泌体后可上调其海马神经元的mi R-26a表达水平,促进其海马神经元增殖,改善大鼠抑郁样行为表现。此外,BMSCs的外泌体可通过提高MDD大鼠血清与海马神经元中的血清超氧化物歧化酶水平并使丙二醛、乳酸脱氢酶、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白介素-1β(interleukin-1β,IL-1β)水平降低来减少其应激与炎症反应[36]。

  表2 骨源细胞的中枢调控作用
表2 骨源细胞的中枢调控作用

  慢性心理压力可上调小鼠PVN神经元单核细胞趋化蛋白1和CC趋化因子受体2(CC chemokine receptor 2,CCR2)表达,进而诱导BMDML浸润PVN[41]。BMDML浸润PVN后高度表达促炎因子IL-1β并激活PVN神经元白细胞介素-1受体和谷氨酸受体的磷酸化,进而调控PVN的神经元传递功能并诱发小鼠抑郁和焦虑样行为[41]。

  2.4、 骨源细胞与帕金森氏病

  在1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的PD小鼠模型中,骨髓衍生细胞(bone marrow derived cell,BMDC)由脑膜、脉络丛向CNS的渗透增加,在整个脑膜、脉络丛、黑质纹状体和海马附近均可观察到细胞簇形式的被荧光标记后的BMDC[29]。经检测脑实质中的大多数BMDC是小胶质细胞,在MPTP诱导PD的过程中,BMDML可通过上调i NOS途径加速小鼠黑质细胞的变性,但亦可介导神经源性神经营养素(neurogenic neurotrophins,NTN)传递保护黑质多巴胺能神经元免受神经毒素影响[29,40]。该实验结果显示,在PD小鼠中BMDML对中枢整体起积极作用,表现为阻止黑质及纹状体神经元变性,增加纹状体新突触形成并改善小鼠运动功能障碍。此外,注射BMSCs分泌组可改善6-轻基多巴诱导的PD动物的精细运动功能障碍并显着减少纹状体多巴胺神经元损伤,其作用机制可能与BMSCs产生的外泌体或组蛋白有关[37]。

  2.5 、骨源细胞与神经性疼痛

  神经性疼痛(neuropathic pain,NPP)是由身体感觉系统病变或疾病引起的疼痛[42]。周围神经损伤可激活中枢BMDML的p38丝裂原活化蛋白激酶通路,进而释放IL-1β、TNF-α等促炎因子产生疼痛超敏反应[43]。NPP小鼠杏仁核中聚集的BMDML与其自身焦虑样行为相关,在杏仁核聚集的BMDML高度表达IL-1β和CCR2,将IL-1β受体拮抗剂直接注射到杏仁核中可逆转NPP小鼠的焦虑样行为,口服CCR2拮抗剂可减少聚集在杏仁核中的BMDML数量,并逆转小鼠焦虑样行为对机械刺激的超敏反应[44]。

  3 、展望

  随着人们对骨骼研究的深入,骨骼对大脑发育和病理生理的调节作用已得到广泛认可,但其在中枢神经系统中的调控功能及机制尚未充分阐明。结合国内外的最新研究发现,后续研究内容可围绕以下方面展开:(1)研究并总结骨源性活性物质作用的中枢脑区定位及其在不同生理、病理生理条件下的变化规律;(2)结合内源性调控和外源性药理学干预技术,明确骨源性活性物质和骨髓来源细胞对不同神经精神疾病的调节作用;(3)明确在中枢神经系统内与骨源活性物质结合并发挥生理效应的受体;(4)探求骨骼通过血液循环的分泌途径参与其它组织器官的功能调节对中枢调控功能造成影响的机制;(5)考虑到两者来源相同,骨源活性物质和骨源细胞在神经精神疾病发生发展中是否存在交叉或协同作用也值得深入研究。目前,神经精神疾病与脑-骨轴关系的研究仍处于初期阶段,而深入了解神经精神疾病和脑-骨轴之间的关系和作用机制有助于为寻找相关神经精神疾病的干预靶点、建立新型防治策略提供依据。

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