Chinese Journal of Tissue Engineering Research ›› 2015, Vol. 19 ›› Issue (2): 283-288.doi: 10.3969/j.issn.2095-4344.2015.02.023
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Wu Xiao-ying, Yang Bin
Received:
2014-12-18
Online:
2015-01-08
Published:
2015-01-08
Contact:
Yang Bin, M.D., Professor, Plastic Surgery Hospital (Institute), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100144, China
About author:
Wu Xiao-ying, Studying for master’s degree, Plastic Surgery Hospital (Institute), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100144, China
CLC Number:
Wu Xiao-ying, Yang Bin . Brain-derived neurotrophic factor in the development and metabolism of bone and tooth: promoting or inhibiting proliferation and differentiation?[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(2): 283-288.
2.1 脑源性神经营养因子与TrkB、p75NTR受体 2.1.1 脑源性神经营养因子 在成功发现神经生长因子的存在及促进神经细胞存活功能后,激励了学者们进一步探讨神经细胞所分泌的细胞因子,1982年,Barde等[7]成功的自猪脑提纯了一种新的神经分泌因子,即脑源性神经营养因子。核苷酸系列分析显示脑源性神经营养因子与神经生长因子结构具有相似性[8]。与其他神经营养因子相同,脑源性神经营养因子在人体内可分为两种形态存在:脑源性神经营养因子前体蛋白和成熟脑源性神经营养因子。脑源性神经营养因子前体蛋白的相对分子质量在26 000-28 000之间,肽链长度为247个氨基酸。当在粗面内质网合成后,脑源性神经营养因子前体蛋白被包装入分泌囊泡,在囊泡内由前体蛋白转换酶加工,在其序列第57和58位点进行剪切,将脑源性神经营养因子分裂为成熟脑源性神经营养因子和前体肽两个片断,共同分泌出细胞[9]。有时脑源性神经营养因子前体蛋白并不在囊泡内进行剪切,而是在细胞外由纤溶酶和基质金属蛋白酶进行加工[10]。成熟脑源性神经营养因子的肽链长度为119个氨基酸,相对分子质量为13 500,以二聚体形态存在[11]。成熟脑源性神经营养因子可与TrkB受体高亲性地结合,并与另一受体,p75NTR,低亲和性结合。脑源性神经营养因子前体蛋白则与成熟脑源性神经营养因子具有不同的分子生物学作用,与p75NTR高亲和性结合,还可与TrkB受体和分拣蛋白结合[12]。在Wool等的神经细胞的突触可塑性试验中,脑源性神经营养因子前体蛋白结合p75NTR受体,增强海马C1区的长时程抑制[13],而成熟脑源性神经营养因子则是维持长时程增强[14],也显示了两者不同的作用。 2.1.2 TrkB受体 成熟脑源性神经营养因子与TrkB高亲性结合,目前研究显示脑源性神经营养因子大部分分子生物学作用均与该受体有关[3,14-15]。TrkB属于原肌原蛋白相关激酶家族,可与脑源性神经营养因子及NT3/4结合。由3个Ⅰ型单跨膜蛋白组成,在胞外具有3个富含半胱氨酸域二个富含亮氨酸域和两个免疫球蛋白位点,胞内具有一个酪氨酸激酶域[15],并藉由免疫球蛋白位点与其配体结合[16]。对mRNA不同的剪切方式,可使细胞合成不同的TrkB异构体,分别对NT-3/4与脑源性神经营养因子特异性结合[17]。 TrkB启动信号通路的机制与脑源性神经营养因子结合的酪氨酸残基磷酸化有关。这些磷酸化酪氨酸位点可提供效应蛋白停泊位点,使之启动核内信号通路。以下简单介绍TrkB涉及的几个信号通路。①PLC-γ信号通路:TrkB受体的Y785酪氨酸残基磷酸化后[18],召集并启动了PLC-γ。PLC-γ磷脂酰肌醇-4,5-二磷酸(PI(4,5)P2)水解成甘油二酯(DAG)与三磷酸酯(IP3)[19]。三磷酸酯导致胞内钙离子释放,激活钙依赖蛋白酶。同时,钙离子释放与甘油二酯的产生激活了蛋白激酶C,进而通过Raf启动下游ERK信号通路。②PI3K信号通路:TrkB受体的酪氨酸残基被磷酸化后,形成一个Shc结合位点,Shc与Grb2结合形成复合体,激活磷脂酰肌醇3-激酶(PI3K)并磷酸化肌醇磷脂,使局部细胞膜结构改变,促进PDK1与其底物Akt转入细胞内并激活Akt。活化的Akt藉由磷酸化促凋亡蛋白Bad、Caspase 9、Iκ B kinase调控细胞存活[20]。③ERK信号通路:ERK信号通路是PLC-γ与PI3K-Akt的下游通路。当激活ERK通路后,形成了Grb2与Ras激活物SOS的复合体,激活Ras及c-Raf/MEK/ERK级联反应[20]。 2.1.3 p75NTR受体p75NTR,又称神经生长因子受体,属于肿瘤坏死因子受体家族,除了广泛表达于神经与非神经组织外,近年来,p75NTR还被发现表达脂肪干细胞、牙髓干细胞表面[21-22],被认为可能是间充质干细胞标记物之一,又称CD271。p75NTR可透过其位于胞外的4个富含半胱氨酸区域与所有神经营养因子结合[23],而其胞内结构域与同家族的肿瘤坏死因子受体及Fas抗原相似[24]。 p75NTR被认为与细胞凋亡有关,许多证据显示细胞因子与p75NTR结合后,激活JNK通路,上调p53,启动细胞凋亡[25]。此外,如前所述,脑源性神经营养因子前体蛋白与p75NTR结合,同时会与P75NTR共受体分拣蛋白结合,形成高亲和力的蛋白复合体,从而促进细胞程序性死 亡[12]。虽然TrkB受体与p75NTR受体并没有直接相互结合,但有证据显示两者间存在复合体形态[26],并作为一个转换因子,增加TrkB受体对脑源性神经营养因子的特异性[26]。另有研究表示,p75NTR受体可能藉由延长Trk受体在细胞表面的表达,增强了Trk受体介导的细胞存活通路[27]。 总体而言,由成熟神经营养因子共同激活Trk与p75NTR受体可促进细胞存活,而在单独激活p75NTR的情况下,则通常促进细胞死亡。然而,这可能因发生在不同细胞类型而有所不同。 2.2 脑源性神经营养因子与骨组织 那么脑源性神经营养因子具体在骨发育及重建过程中扮演何种作用呢?查阅文献发现脑源性神经营养因子在骨发育、创伤及病理情况下表现略有不同,但总体而言具有促进成骨与钙化的能力。以下将从5方面进行阐述。 2.2.1 脑源性神经营养因子、TrkB与骨 在2001年,Yamashiro等[28]首次应用原位杂交和免疫组织化学技术,在成骨细胞和软骨细胞中发现脑源性神经营养因子、TrkB的mRNA及脑源性神经营养因子蛋白的表达,从而开启了人们对于脑源性神经营养因子在骨组织方面的研究。有趣的是,在小鼠股骨生长板、下颌髁状突、松质骨表面和骨膜表面等成骨发生处,在活动期成骨细胞中可检测到大量的脑源性神经营养因子、TrkB的mRNA表达,然而在静止期成骨细胞中却无法检测到或仅能测得少量mRNA表达。研究表明成骨细胞在活动期合成脑源性神经营养因子和TrkB的mRNA,可能协助其分泌类骨质。脑源性神经营养因子和TrkB的mRNA也表达于股骨生长板和下颌髁状突软骨的软骨增殖区、软骨肥大区和成熟区中。随后,Hutchison[29]利用牛生长板初级软骨细胞及小鼠ATDC5细胞进行体外实验时进一步发现,脑源性神经营养因子通过与胰岛素样生长因子1协同激活p38-MAPK通路,促进初级软骨细胞分化;并可藉由抑制p38相关因子raf-1激酶抑制ERK通路,从而抑制软骨细胞增殖。这提示脑源性神经营养因子可藉由调节ERK/p38活性比调控软骨的分化、增殖。Hutchison[30]的动物实验更显示,条件敲除TrkB及p38α同种型基因可使小鼠出现相似的侏儒样表现,表现为长骨及脊柱长度明显短于正常小鼠。组织学检查显示这两类小鼠的生长板宽度均明显变窄,其中TrkB敲除小鼠主要表现于软骨肥大区的变窄,而p38α敲除小鼠则为主要为软骨增殖区和软骨肥大区。检测两种小鼠的Runx2和Sox9转录因子表达均大幅下降。同时,TrkB敲除小鼠生长板的p38蛋白明显减少,而p38α敲除小鼠中TrkB的表达仍然存在,显示脑源性神经营养因子可能透过TrkB/p38通路,调节Runx2及Sox9表达,最终影响骨骼发育。 2.2.2 p75NTR与骨 除了TrkB外,p75NTR似乎也参与骨发育的过程中。Alexander等[31]实验证明,在p75NTR可在人下颌骨膜细胞诱导成骨的过程早期表达,而且表达p75NTR的骨膜细胞较无表达者具有更高的碱性磷酸酶转录水平,显示p75NTR可作为提示细胞钙化潜能的早期标记物。Mikami等[32]在鼠前成骨细胞系MC3T3-E1的实验中使p75NTR过度表达,结果显示过度表达p75NTR的MC3T3-E1细胞增殖与分化能力明显增强,并在诱导第14天出现锌指结构样的转录因子、骨钙蛋白和骨唾液酸蛋白表达增强,碱性磷酸酶活性也明显增强。这一诱导作用,可被Trk受体非特异性拮抗剂K252a抑制。Akiyama等[33]实验通过比较鼠前成骨细胞系MC3T3-E1与人成骨细胞系MG63也获得了同样的结果,显示p75NTR是在分化后期促进锌指结构样的转录因子表达上升进而促进成骨;而其促进增殖作用可通过与NgR受体的交互作用调控。此外,在MC3T3-E1 与MG63细胞中均可于细胞表面测得Trk受体,并可同样藉由K252a抑制p75NTR促进细胞分化的作用。然而Mikami等[22]另一实验显示,p75NTR单独在间充质干细胞表达时,则抑制间充质向骨细胞与分化,下调骨唾液酸蛋白表达水平。值得一提的是,p75NTR的表达随着间充质干细胞培养时间增长逐渐减弱,提示p75NTR单独表达能保持干细胞的多能性。然而间充质干细胞表面并未测得Trk受体,且p75NTR的抑制作用并不受Trk受体拮抗剂影响。上述实验提示p75NTR对成骨分化的作用可能受不同细胞类型及该细胞是否表达Trk受体影响,两种受体间如何相互作用则尚待进一步研究。 2.2.3 脑源性神经营养因子与骨修复 脑源性神经营养因子在骨折愈合中也有一定作用。Asaumi等[34]在小鼠肋骨骨折实验中发现脑源性神经营养因子可在近骨小梁膜内成骨处的成骨细胞中表达,并在骨折后第8天达到高峰。然而,该实验中并未在骨折组织中测得TrkB受体表达。Kilian等[35]则在人骨折早期血肿的造血细胞、肉芽组织中的成纤维细胞及活化的成骨细胞中均检测到脑源性神经营养因子及TrkB受体,显示其作用贯穿整个骨折愈合过程。龙雄武[36]的研究也显示,合并脑外伤的胫骨骨折小鼠的成骨细胞和软骨细胞的脑源性神经营养因子与TrkB表达较早达到高峰,合并脑损伤的胫骨骨折小鼠骨折线愈合较单纯骨折者早,骨折处塑形较好。Aiga等[37]在小鼠股骨牵引延长的实验中则发现,牵引早期中可于软骨骨化处的软骨细胞与成骨细胞中测得脑源性神经营养因子及TrkB,牵引晚期与巩固期则可于膜内成骨处测得,且脑源性神经营养因子mRNA表达持续增高。上述研究结果提示在骨创伤中,脑源性神经营养因子及TrkB表达上调,并可促进成骨细胞及软骨细胞活动,增进骨折愈合与新骨形成。 2.2.4 脑源性神经营养因子与内分泌 脑源性神经营养因子除了本身对于骨组织的作用外,似乎也可通过与激素的作用影响骨组织代谢。Camerino等[38]敲除小鼠神经系统来源的脑源性神经营养因子基因,保留其他 细胞来源的脑源性神经营养因子后,小鼠表现为骨密度增高,在骨皮质与骨松质均有明显增加,同时伴有肥胖、贪食,体内瘦素水平升高,类似于瘦素缺陷型小鼠。这可能是由于脑源性神经营养因子敲除使外周瘦素水平升高,对成骨细胞作用,使骨密度升高。有趣的是,在Camerino等[38]实验中,雌性小鼠在6个月大时可见明显成骨细胞周长增大,而雄性小鼠则无成骨细胞周长增大或成骨细胞数量的表现。而Hutchison[30]的实验中,雌性小鼠侏儒样表现更为严重,生长板宽度也较雄性小鼠窄。这可能与雌激素与脑源性神经营养因子的相互作用有关。 2.2.5 其他 另外,Deng等[39]的研究显示,脑源性神经营养因子的不同等位基因,可能影响蛋白激酶CHEK2对脑源性神经营养因子氨基酸残基T62位点的磷酸化,调控骨桥蛋白、骨形成蛋白2、碱性磷酸酶等成骨相关基因表达,进而影响骨生成。在人群中,具有脑源性神经营养因子次要等位基因(A)的人的骨密度较主要等位基因(G)的人低。这一现象普遍共存于高加索人与汉人中。 2.3 脑源性神经营养因子与多发性骨髓瘤 脑源性神经营养因子在多发性骨髓瘤的作用中则较为特殊。多发性骨髓瘤是一种由来源于B细胞的浆细胞在骨髓中克隆性生长的血液性肿瘤,最主要的表现是由于临近骨髓瘤的成骨与破骨细胞异常活动所造成的严重骨组织损害,而破骨细胞增殖与活动及骨髓血管新生是促进发展的原因之一[40]。近年来有研究显示多发性骨髓瘤患者血浆中脑源性神经营养因子水平较一般人明显升高[41],提示脑源性神经营养因子可能参与其疾病发展过程中。 孙春艳等[42]研究证实,来源于多发性骨髓瘤的浆细胞高度表达脑源性神经营养因子,并通过与TrkB受体结合,促进肿瘤细胞生长、存活与移行。此外,多发性骨髓瘤来源的脑源性神经营养因子可结合于成骨细胞的TrkB受体,经TrK/ERK通路,激活下游RANKL信号通路,并抑制骨保护素表达[43]。RANKL信号通路可激活破骨细胞,而骨保护素可竞争性与RANK结合,从而抑制破骨细胞分化与活动[44]。脑源性神经营养因子还具有促进血管新生的作用。实验显示,脑源性神经营养因子通过激活PI3K/Akt及ERK通路,增加血管内皮生长因子的生成与毛细血管密度,促进内皮细胞存活[45]。王雅丹等[46]则将抗脑源性神经营养因子单克隆抗体应用于骨髓瘤异体移植动物模型,结果显示脑源性神经营养因子单克隆抗体可有效缩小肿瘤体积,降低瘤组织微血管密度,显著抑制体外RPMl8226细胞的增殖和诱导内皮细胞血管新生。这也证实了脑源性神经营养因子在骨髓瘤中具有促进肿瘤细胞生长、血管新生的作用。 2.4 脑源性神经营养因子与牙、牙周 2.4.1 脑源性神经营养因子与牙组织 脑源性神经营养因子在再生牙科医学同样也引起关注。Mitsiadis等[6]的研究指出在牙发生过程中可发现神经营养因子及受体表达,提示脑源性神经营养因子及其他神经营养因子可能影响成牙本质细胞分化。而Mizuno等[47]的研究则显示脑源性神经营养因子在体外可促进牙髓干细胞分化为成牙本质细胞。值得一提的是,脑源性神经营养因子对牙髓干细胞的增殖作用并非剂量相关,这点与王晓东等[48]的研究结果相符。其原因可能为细胞增殖与分化过程中需要不同的细胞因子剂量,低浓度的细胞因子具有增殖作用,高浓度的细胞因子则促进细胞分化。 脑源性神经营养因子在牙发育中也可促进骨桥蛋白、骨形成蛋白2、碱性磷酸酶等骨相关蛋白表达。研究表明,在脑源性神经营养因子作用下,牙髓干细胞、成牙骨质细胞的骨相关蛋白表达含量均明显上升[47,49]。Kajiya等[49]利用siRNA分别干扰成牙骨质细胞的TrkB受体及p75NTR受体表达,发现不表达TrkB受体者脑源性神经营养因子作用的骨相关蛋白表达明显下降,而不表达p75NTR受体者则无明显改变,提示TrkB受体参与其过程。进一步研究发现[49],脑源性神经营养因子与TrkB受体结合后启动ERK信号通路,磷酸化转录因子Elk-1,从而上调骨相关蛋白基因表达。 2.4.2 脑源性神经营养因子与牙周组织 此外,在牙周组织研究中, Kurihara等[50]发现牙周膜细胞可合成分泌脑源性神经营养因子,表达TrkB的mRNA,并受到炎症因子调节,提示脑源性神经营养因子可能在牙周炎发生中起到一定作用。由于牙周膜细胞在脑源性神经营养因子作用下同样可以表达骨相关蛋白,具有成骨活性并抑制破骨细胞生成[51],并且脑源性神经营养因子具有促血管新生及促神经分布能力,Takeda等[51]尝试将其应用于牙周组织再生的研究中。实验结果发现,脑源性神经营养因子可促进牙周膜细胞增殖并分泌骨桥蛋白、骨形成蛋白2、碱性磷酸酶、Ⅰ型胶原酶,成功使牙槽骨、牙骨质及牙周膜等牙周组织再生。Jimbo等[52]、Takeda等[53]联合应用高分子透明质酸作为支架,修复牙根分叉缺损,均取得良好的再生效果。"
[1] Imai S, Tokunaga Y, Maeda T, et al. Calcitonin gene-related peptide, substance P, and tyrosine hydroxylase- immunoreactive innervation of rat bone marrows: an immunohistochemical and ultrastructural investigation on possible efferent and afferent mechanisms.J Orthop Res. 1997;15(1):133-140. [2] Hohn A, Leibrock J, Bailey K, et al. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990; 344(6264):339-341. [3] Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci. 2005;6(8):603-614. [4] Reichardt LF.Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci.2006;361(1473): 1545-1564. [5] Matsuda H, Coughlin MD, Bienenstock J, et al. Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci U S A. 1988;85(17): 6508-6512. [6] Mitsiadis TA, Luukko K. Neurotrophins in odontogenesis. Int J Dev Biol.1995;39(1):195-202. [7] Barde YA, Edgar D, Thoenen H.Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982; 1(5): 549-553. [8] Leibrock J, Lottspeich F, Hohn A, et al. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989; 341(6238):149-152. [9] Seidah NG, Benjannet S, Pareek S, et al. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett.1996;379(3): 247-250. [10] Lee R, Kermani P, Teng KK, et al.Regulation of cell survival by secreted proneurotrophins. Science. 2001;294(5548): 1945-1948. [11] Radziejewski C, Robinson RC, DiStefano PS, et al. Dimeric structure and conformational stability of brain-derived neurotrophic factor and neurotrophin-3. Biochemistry. 1992; 31(18):4431-4436. [12] Teng HK, Teng KK, Lee R, et al.ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 200525(22):5455-5563. [13] Woo NH, Teng HK, Siao CJ, et al.Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Peptides. Nat Neurosci. 2005;8(8):1069-1077. [14] Kang H, Welcher AA, Shelton D,et al.Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron.1997;19(3):653-64. [15] Windisch JM, Marksteiner R, Lang ME, et al.Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 bind to a single leucine-rich motif of TrkB. Biochemistry.1995; 34(35):11256-11263. [16] Ultsch MH1, Wiesmann C, Simmons LC, et al. Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol. 1999;290(1):149-159. [17] Boeshore KL,Luckey CN,Zigmond RE,et al.TrkB isoforms with distinct neurotrophin specificities are expressed in predominantly nonoverlapping populations of avian dorsal root ganglion neurons. J Neurosci. 1999;19(12):4739-4747. [18] Obermeier A, Bradshaw RA, Seedorf K, et al. Neuronal differentiation signals are controlled by nerve growth factor receptor/Trk binding sites for SHC and PLC gamma. EMBO J. 1994;13(7):1585-1590. [19] Vetter ML, Martin-Zanca D, Parada LF, et al. Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk protooncogene.Proc Natl Acad Sci U S A. 1991;88(13):5650-5654. [20] Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol.2002;67(3):203-233. [21] Yamamoto N, Akamatsu H, Hasegawa S, et al. Isolation of multipotent stem cells from mouse adipose tissue.J Dermatol Sci. 2007;48(1):43-52. [22] Mikami Y, Ishii Y, Watanabe N, et al. CD271/p75(NTR) inhibits the differentiation of mesenchymal stem cells into osteogenic, adipogenic, chondrogenic, and myogenic lineages. Stem Cells Dev. 2011;20(5):901-913. [23] Baldwin AN, Shooter EM. Zone mapping of the binding domain of the rat low affinity nerve growth factor receptor by the introduction of novel N-glycosylation sites.J Biol Chem. 1995;270(9):4594-4602. [24] Chapman BS.A region of the 75 kDa neurotrophin receptor homologous to the death domains of TNFR-I and Fas.FEBS Lett. 1995;374(2):216-220. [25] Aloyz RS, Bamji SX, Pozniak CD, et al. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.J Cell Biol.1998;143(6):1691-1703. [26] Bibel M, Hoppe E, Barde YA. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR.EMBO J. 1999;18(3):616-622. [27] Makkerh JP, Ceni C, Auld DS, et al. p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation.EMBO Rep. 2005;6(10):936-941. [28] Yamashiro T, Fukunaga T, Yamashita K, et al. Gene and protein expression of brain-derived neurotrophic factor and TrkB in bone and cartilage.Bone. 2001;28(4):404-409. [29] Hutchison MR. BDNF alters ERK/p38 MAPK activity ratios to promote differentiation in growth plate chondrocytes.Bone. Mol Endocrinol. 2012;26(8):1406-1416. [30] Hutchison MR. Mice with a conditional deletion of the neurotrophin receptor TrkB are dwarfed, and are similar to mice with a MAPK14 deletion.PLoS One. 2013;8(6):e66206. [31] Alexander D, Schäfer F, Munz A, et al.LNGFR induction during osteogenesis of human jaw periosteum-derived cells.Cell Physiol Biochem. 2009;24(3-4):283-290. [32] Mikami Y, Suzuki S, Ishii Y, et al. The p75 neurotrophin receptor regulates MC3T3-E1 osteoblastic differentiation. Differentiation. 2012;84(5):392-399. [33] Akiyama Y, Mikami Y, Watanabe E, et al.The P75 neurotrophin receptor regulates proliferation of the human MG63 osteoblast cell line.Differentiation. 2014;87(3-4):111-118. [34] Asaumi K, Nakanishi T, Asahara H, et al. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone. 2000;26(6):625-633. [35] Kilian O, Hartmann S, Dongowski N, et al. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone. 2000;26(6):625-633. [36] 龙雄武.脑外伤合并骨折时脑源性神经营养因子对骨折愈合的影响[D].中南大学.外科学(骨科) , 2010. [37] Aiga A, Asaumi K, Lee YJ, et al. Expression of neurotrophins and their receptors tropomyosin-related kinases (Trk) under tension-stress during distraction osteogenesis.Acta Med Okayama. 2006;60(5):267-277. [38] Camerino C, Zayzafoon M, Rymaszewski M, et al. Central depletion of brain-derived neurotrophic factor in mice results in high bone mass and metabolic phenotype.Endocrinology. 2012;153(11):5394-5405. [39] Deng FY, Tan LJ, Shen H, et al. SNP rs6265 regulates protein phosphorylation and osteoblast differentiation and influences BMD in humans.J Bone Miner Res. 2013;28(12):2498-2507. [40] Roodman GD.Pathogenesis of myeloma bone disease. J Cell Biochem. 2010 Feb 1;109(2):283-291. [41] 王雅丹,胡豫,魏文宁,等.脑源性神经营养因子在多发性骨髓瘤患者血浆中的表达[J].临床血液学杂志,2004,17(2):82-83,86. [42] 孙春艳,胡豫,吴涛,等.脑源性神经营养因子及其受体在多发性骨髓瘤细胞中的表达及意义[J].中华内科杂志,2005,44(12):906-909. [43] Ai LS, Sun CY, Wang YD, et al. Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo.Int J Cancer. 2013; 133(5):1074-1084. [44] Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Cell. 1997 Apr 18;89(2):309-319. [45] Sun CY, Hu Y, Huang J, et al. Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling.Tumour Biol. 2010;31(2):121-128. [46] 王雅丹,胡豫,黄靖,等.抗脑源性神经营养因子单克隆抗体在骨髓瘤异体移植动物模型中的抗肿瘤效应[J]. 中国实验血液学杂志. 2008;16(5):1069-1072. [47] Mizuno N, Shiba H, Xu WP, et al. Effect of neurotrophins on differentiation, calcification and proliferation in cultures of human pulp cells.Cell Biol Int. 2007;31(12):1462-9. [48] 王晓东,王捍国,倪龙兴.脑源性神经营养因子在人牙髓干细胞中的表达及其对细胞增殖分化的影响[J].牙体牙髓牙周病学杂志. 2009;19(5):247-250. [49] Kajiya M, Shiba H, Fujita T, et al. Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts.J Biol Chem. 2008;283(23): 16259-16267. [50] Kurihara H, Shinohara H, Yoshino H, et al. Neurotrophins in cultured cells from periodontal tissues.J Periodontol. 2003; 74(1):76-84. [51] Takeda K, Shiba H, Mizuno N, et al. Brain-derived neurotrophic factor enhances periodontal tissue regeneration. Tissue Eng. 2005;11(9-10):1618-1629. [52] Jimbo R, Tovar N, Janal MN, et al. The effect of brain-derived neurotrophic factor on periodontal furcation defects.PLoS One. 2014;9(1):e84845. [53] Takeda K, Sakai N, Shiba H, et al. Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration.Tissue Eng Part A. 2011;17(7-8):955-967. |
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