Chinese Journal of Tissue Engineering Research
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Zhao Zheng-ju1, Luo Ju-ying2, Cheng Hao1, Xiao Qiang1
Revised:
2013-10-16
Online:
2013-12-10
Published:
2013-12-10
Contact:
Luo Ju-ying, Master, Associate professor, Associate chief nurse, School of Nursing, Hubei University of Science and Technology, Xianning 437100, Hubei Province, China
About author:
Zhao Zheng-ju★, Master, Associate professor, Associate chief physician, Department of Surgery, Clinical College of Hubei University of Science and Technology, Xianning 437100, Hubei Province, China
zhaozhengju@sohu.com
Supported by:
the Guidance Project of the Science and Technology Department, Hubei Provincial Bureau of Education, No. B2013054*
CLC Number:
Zhao Zheng-ju, Luo Ju-ying2, Cheng Hao, Xiao Qiang. Anti-tumor necrosis factor alpha therapy avoids bone damage in patients with chronic arthritis: Who can authenticate it?[J]. Chinese Journal of Tissue Engineering Research, doi: 10.3969/j.issn.2095-4344.2013.50.018.
2.1 破骨细胞发生 破骨细胞发生是一个破骨细胞增殖和成熟的过程,而其前体细胞来源于骨髓。在合适的生理条件下,RANKL和RANK的相互作用对破骨细胞的发生进行主要调节。RANKL是一种破骨细胞膜上的糖蛋白经金属蛋白酶蛋白水解所得到的可溶性因子。RANK为一种Ⅰ型跨膜受体表达于骨髓巨噬细胞,它能诱导骨髓巨噬细胞分化为破骨细胞。RANKL/RANK系统引发了一种级联放大的发射信号,这种级联放大的信号的特点是RANK的三聚体和肿瘤坏死因子受体相关因子6(TRAF6)的活化,刺激NF-κB以及丝裂原活化蛋白激酶MAPKs(JNK和p38)后,参与转录因子c-Fos、c-Src、MITF的激 活[11]。促破骨细胞发生级联信号的特点是参与的因子比较多,包括FHL2(结合TRAF6后可对RANK-RANKL复合物进行负反馈调节)、分子支架Gab2、AP-1转录因子复合体[12]。 另一个在破骨细胞生成重要的介导物质是FcRγ、DAP12、免疫球蛋白样受体[13-14]。免疫球蛋白样受体中,触发受体表达于骨髓细胞-2(TREM-2)并与信号调节蛋白β(一个信号调节蛋白β)DAP12结合[15]。几个破骨细胞特异基因受到NFATc1核因子以及其他转录因子AP-1、MITF的影响, NFATc1的活性受到磷脂酶Cc(PLCc)的控制,经细胞内钙离子的释放,NFATc1又反过来被RANK激活[15-16]。通过 TRAF6、NF-κB以及c-Fos诱导作用,RANKL刺激NFATc1。而NFATc1在破骨细胞生成时存在一些独立性的作用,且已得到证实,体外培养实验的证据显示NFATc1缺陷的胚胎干细胞无法分化为破骨细胞,这也表明骨髓前体细胞时NFATc1相关破骨细胞发生过程,并不需要RANKL的参与[16]。 骨保护素(OPG)是一种来自于超家族肿瘤坏死因子受体的分泌糖蛋白,且为RANKL最主要的负反馈调节物质。它是一种破骨细胞产生的前肽,从380个氨基酸成熟肽中21个氨基酸裂解后产生的。它是一种RANKL的可溶性引诱物受体,可在破骨细胞的细胞膜上竞争性地抑制RANKL、RANK结合,因此它可以抑制RANK的激活以及抑制随后的破骨细胞生成。denosumab为RANKL人类单克隆抗体的反受体激活剂,能直接抑制RANK/RANKL信号发送通路,可能存在控制RANKL产物的功能[17]。Denosumab结合失去活性的人类RANKL,则发现其类似于骨保护素。临床研究表明denosumab具有安全性,若用于绝经后骨质疏松症、转移所致骨质破坏、类风湿性关节炎患者能够产生抗骨吸收作用[17]。 除了RANK-RANKL复合物外,其他一些促破骨发生因子,如肿瘤坏死因子α、白细胞介素1、白细胞介素6、白细胞介素7、白细胞介素11、白细胞介素17、巨噬细胞集落刺激因子(M-CSF)、转化生长因子β(TGF-β)可在RANKL相关破骨细胞发生中发挥作用[18-19]。除了RANK的信号发送外,重组人白细胞介素 23也参与了破骨细胞发生,在巨噬细胞集落刺激因子分化为人外周血单核细胞的研究中,发现其过程依赖于白细胞介素17和骨保护素[20]。此外,很多趋化因子如巨噬细胞炎性蛋白1α(MIP-1α)、MIP-1β、干扰素γ诱导蛋白10(IP-10即CXCL10)、干扰素γ所诱导的单核因子,在破骨细胞分化中起到重要的作用[21-22]。 独立于这些因子之外,还存在一种破骨细胞的“协同刺激系统”。也就是破骨细胞相关性受体(OSCAR),它是白细胞受体复合物成员,被表达于破骨细胞、单核细胞、树状突细胞。破骨细胞相关性受体负责诱导——通过一种添加方式RANKL原发性刺激分化破骨细胞。RANKL和巨噬细胞集落刺激因子不能直接刺激破骨细胞相关性受体的表达,而是由肿瘤坏死因子α诱导的转录因子对其进行上调节;而由MafB和分化抑制因子2则进行下调节[23-25]。破骨细胞相关性受体能够在循环单核细胞、炎症滑膜组织内的单核细胞、滑膜和骨界面内的成熟破骨细胞上进行表达,并负责对RANKL产生刺激。破骨细胞相关性受体的表达程度越高,单核细胞越趋向于分化为破骨细胞[26]。 有些人对Wnt信号通路在慢性关节炎中的作用表现出极大的兴趣,而Wnt信号由一些特殊的糖蛋白组成,这些糖蛋白涉及细胞分化、启动和进展中癌症、骨重塑[27-28]。而且,Wnt信号通路的糖蛋白已经在类风湿性关节炎患者的关节中被分离出来[29]。小鼠中的研究也发现肿瘤坏死因子α可以诱导产生Wnt的抑制剂dickkopf-1(Dkk-1),其表达于小鼠的关节炎模型中[30]。抗-Dkk-1单克隆抗体用于小鼠关节炎模型,发现骨侵蚀、关节结构损伤、炎性骨质损失全部减少,但是却不能减少骨赘的形成。这些研究暗示对DKK-1的抑制一方面增加成骨细胞的发生,另一方面经骨保护素下调节方式减少破骨细胞介导的骨形成。 2.2 肿瘤坏死因子α的作用 在破骨细胞发生的过程中,肿瘤坏死因子α与RANK/RANKL系统相互作用非常紧密。一方面,肿瘤坏死因子α刺激滑膜细胞、T细胞以及破骨细胞后对RANKL进行表达;另一方面,RANKL在体外诱导肿瘤坏死因子α表达,即使在RANKL缺乏以致不能对破骨细胞生成进行诱导。但肿瘤坏死因子α结合2种受体后能够发挥它的生物效能,一种是Ⅰ型肿瘤坏死因子受体(TNFRⅠ);另一种是Ⅱ型肿瘤坏死因子受体(TNFRⅡ)。只有结合失活的抗-TNFRⅠ受体抗体,而不是结合抗-TNFRⅠ受体抗体,才能导致对破骨细胞发生(RANKL诱导)产生抑制作用。这表明,在RANKL诱导破骨细胞发生时,TNFRⅠ独自发挥了关键性的作用。被广泛接受的观点是,在破骨细胞激活过程中肿瘤坏死因子α与RANKL彼此影响,即使在RANK缺乏时,肿瘤坏死因子α也可以诱导破骨细胞的发生过程。事实上,在体外和小鼠的研究中,推测缺乏RANK时肿瘤坏死因子α对骨细胞发生的过程中存在一种作用。但发现肿瘤坏死因子α在破骨细胞生成中的作用是通过直接剌激的方式(将巨噬细胞置于足量水平的RANKL环境中,并加入对RANK起协同刺激作用的受体PIR-A)[31]。肿瘤坏死因子α介导破骨细胞机制还不为人所知。推测肿瘤坏死因子α对RANKL的产物进行诱导,是通过间接影响破骨细胞发生对间质细胞的支持,以及经RANK,TRAF6,NF-κB(这些因子早期破骨细胞分化时被激活)的表达和活化后直接影响破骨前体细胞[31]。而令人感到矛盾的是,使用RANKL和巨噬细胞集落刺激因子刺激破骨细胞前体细胞并进行培养,发现在分化后期,肿瘤坏死因子α参与破骨细胞分化显得非常明显。其特征为钙离子诱导的NFATc1过度表达[16]。诱导免疫球蛋白样受体PIR-A是协同刺激RANK的受体,还参与了钙离子信号的发送。经PIR-A诱导,肿瘤坏死因子α刺激了破骨细胞前体细胞[15,32]。 推测:仅仅只有溶解的肿瘤坏死因子α在破骨细胞发生时发挥了作用。因为事实上,TNFRⅠ在小鼠上表达比用TNFRⅡ时出现更多数量的破骨细胞,暗示溶解的肿瘤坏死因子α与TNFRⅠ结合诱导破骨细胞发生。TNFRⅡ是相关肿瘤坏死因子α受体中一种具有优先选择性的受体,在破骨细胞发生中有非常重要的作用。而肿瘤坏死因子α刺激破骨前体细胞、骨髓基质细胞表达TNFRⅠ,能产生其他促破骨细胞发生细胞因子,如白细胞介素1、RANKL、巨噬细胞集落刺激因子[18]。 2.3 抗肿瘤坏死因子α治疗慢性关节炎相关骨损伤的作用 在病理学的环境下,PsA、肿瘤坏死因子α在破骨细胞发生具有重要的作用,他们联合其他炎性细胞因子(白细胞介素1、白细胞介素6、白细胞介素17)后参与类风湿性关节炎相关的骨质损伤。而在其他一些慢性关节炎,肿瘤坏死因子α在骨质中起到重要的作用,而不同于它在免疫系统中的作用。实际上,抗肿瘤坏死因子α治疗是能延缓骨质损伤的进展,在无疼痛、炎症临床症状的患者身上[32]。 多项研究表明,抗肿瘤坏死因子α治疗具有非常重要的作用,特别是对于类风湿性关节炎患者关节中的骨质侵蚀和炎症[33]。肿瘤坏死因子α抑制剂要么是一种可溶性受体,如依那西普;要么是一种单克隆抗体,如昔单抗、阿达木。在胶原所致关节炎(CIA)的小鼠应用一种新开发的肿瘤坏死因子α抑制剂(WP9QY肽),其包含一种外环改良的芳香族类似物,其改良处为模仿了参与肿瘤坏死因子α与TNFR的相互作用关键部位的三维结构。WP9QY肽只是一种实验性模板研究,也没准备应用于临床。英夫利昔单抗为一种人类和鼠类的嵌合抗体,其能够中和人类肿瘤坏死因子α与小鼠肿瘤坏死因子α。WP9QY肽对比英夫利昔单抗,同等剂量下前者几乎没有什么明显的抗炎作用,但WP9QY肽却明显减少了胶原所致关节炎相关的骨质损伤,并且抑制了其系统性骨质流失。暗示WP9QY肽与英夫利昔单抗所参与抑制肿瘤坏死因子α和RANKL的机制不同[34]。 实际上,WP9QY肽同时对肿瘤坏死因子α和RANKL产生了抑制[35],一些胶原所致关节炎小鼠和肿瘤坏死因子转基因小鼠的对比研究表明,事实上因为抗肿瘤坏死因子抗体和骨保护素的协同参与,产生了肿瘤坏死因子α和RANKL的中和效应[36-37]。此外,RANKL介入的骨吸收,全身骨质流失比在炎症部位的更高。使用鼠类肿瘤坏死因子α诱导的关节炎模型,也发现了类似的效应。研究抗肿瘤坏死因子α治疗对骨代谢的影响,应用依那西普或者英夫利昔单抗治疗类风湿性关节炎的患者,并进行为期12个月的随访研究[38]。采用定量超声获得双手指骨近端的干骺端的骨密度,并应用双能X射线骨密度仪获得髋关节和腰椎的骨密度。推测骨吸收的减少总是伴随着骨生成的增加。这可能是由于破骨细胞活性的下降和成骨细胞活性的增长造成的[38]。一些相关磁共振影像学的研究,进一步证实了抗肿瘤坏死因子α治疗骨损伤的影响[39]。研究发现,肿瘤坏死因子α增加了关节炎中循环的破骨细胞前体(OCPs)的数量。而抗肿瘤坏死因子α因子能减少破骨细胞前体的数量,c-Fms原癌基因能增加破骨细胞前体的数量。此外,在RANKL和肿瘤坏死因子α相关破骨细胞前体分化成为破骨细胞的炎症关节处,破骨细胞前体被聚集。最新的一些研究推测,白细胞介素6在体外成骨细胞中的下调节作用对类风湿性关节炎患者血浆中的影响类似于英夫利昔单抗[40]。白细胞介素6在关节炎相关骨质流失中其到重要的作用,影响破骨细胞的聚集和活化。对于抗肿瘤坏死因子α阻滞剂减少类风湿性关节炎患者的骨质破坏所表现出来的有益效应,白细胞介素6下调节作用能对其作出进一步解释。"
[1] Shiozawa S, Tsumiyama K, Yoshida K,et al.Pathogenesis of joint destruction in rheumatoid arthritis.Arch Immunol Ther Exp (Warsz). 2011;59(2):89-95.[2] Kawabata K, Yamamoto K.Recent advances in the pathogenesis of rheumatoid arthritis.Clin Calcium. 2009 ; 19(3):303-309.[3] Pratt AG, Isaacs JD, Mattey DL.Current concepts in the pathogenesis of early rheumatoid arthritis.Best Pract Res Clin Rheumatol. 2009;23(1):37-48.[4] Bromley M, Woolley DE.Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum. 1984;27(9):968-975.[5] Gravallese EM, Manning C, Tsay A,et al.Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor.Arthritis Rheum. 2000;43(2):250-258.[6] Fox DA.Cytokine blockade as a new strategy to treat rheumatoid arthritis: inhibition of tumor necrosis factor.Arch Intern Med. 2000 ;160(4):437-444.[7] Kmie? Z, Soko?owska I.Role of tumor necrosis factor family ligands in the pathogenesis of rheumatoid arthritis--new therapeutical opportunities.Pol Merkur Lekarski. 2007;22 (130):300-304.[8] Yamamura M.Tumor necrosis factor alpha and beta (TNF-alpha and -beta) in pathogenesis of rheumatoid arthritis.Nihon Rinsho. 2005;63 Suppl 1:145-152.[9] Hussein YM, Mohamed RH, Pasha HF,et al.Association of tumor necrosis factor alpha and its receptor polymorphisms with rheumatoid arthritis in female patients.Cell Immunol. 2011;271(1):192-196.[10] Colucci S, Brunetti G, Cantatore FP,et al.Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFalpha, and IL-7 in an in vitro model derived from human psoriatic arthritis.J Pathol. 2007;212(1):47-55.[11] Kobayashi N, Kadono Y, Naito A,et al.Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis.EMBO J. 2001;20(6):1271-1280.[12] David JP, Sabapathy K, Hoffmann O,et al. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation- dependent and -independent mechanisms.J Cell Sci. 2002; 115(Pt 22):4317-4325.[13] Asagiri M, Takayanagi H.The molecular understanding of osteoclast differentiation.Bone. 2007;40(2):251-264. [14] Takayanagi H.Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems.Nat Rev Immunol. 2007;7(4):292-304.[15] Koga T, Inui M, Inoue K,et al.Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428(6984):758-763.[16] Takayanagi H, Kim S, Koga T,et al.Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.Dev Cell. 2002;3(6):889-901.[17] Pageau SC.Denosumab.MAbs. 2009;1(3):210-215. [18] Wei S, Kitaura H, Zhou P,et al.IL-1 mediates TNF-induced osteoclastogenesis.J Clin Invest. 2005;115(2):282-290.[19] Hase H, Kanno Y, Kojima H,et al.Coculture of osteoclast precursors with rheumatoid synovial fibroblasts induces osteoclastogenesis via transforming growth factor beta-mediated down-regulation of osteoprotegerin.Arthritis Rheum. 2008;58(11):3356-3365.[20] Yago T, Nanke Y, Kawamoto M,et al.IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats.Arthritis Res Ther. 2007;9(5):R96.[21] Abe M, Hiura K, Wilde J, et al. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma.Blood. 2002;100(6):2195-2202.[22] Kwak HB, Ha H, Kim HN,et al.Reciprocal cross-talk between RANKL and interferon-gamma-inducible protein 10 is responsible for bone-erosive experimental arthritis.Arthritis Rheum. 2008;58(5):1332-4132.[23] So H, Rho J, Jeong D,et al.Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression.J Biol Chem. 2003;278(26):24209-24216. [24] Kim K, Kim JH, Lee J,et al.MafB negatively regulates RANKL-mediated osteoclast differentiation.Blood. 2007; 109(8): 3253-3259. [25] Herman S, Müller RB, Krönke G,et al.Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis.Arthritis Rheum. 2008; 58(10): 3041-3050.[26] Polzer K, Diarra D, Zwerina J,et al.Inflammation and destruction of the joints--the Wnt pathway.Joint Bone Spine. 2008;75(2):105-107.[27] Baron R, Rawadi G, Roman-Roman S.Wnt signaling: a key regulator of bone mass.Curr Top Dev Biol. 2006;76: 103-127.[28] Sen M, Lauterbach K, El-Gabalawy H,et al.Expression and function of wingless and frizzled homologs in rheumatoid arthritis.Proc Natl Acad Sci U S A. 2000;97(6):2791-2796.[29] Heiland GR, Zwerina K, Baum W,et al. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression.Ann Rheum Dis. 2010;69(12): 2152-2159. [30] Fuller K, Kirstein B, Chambers TJ.Murine osteoclast formation and function: differential regulation by humoral agents. Endocrinology. 2006;147(4):1979-1985.[31] Kaji K, Katogi R, Azuma Y,et al.Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6.J Bone Miner Res. 2001; 16(9):1593-1599.[32] Smolen JS, Han C, Bala M,et al.Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study.Arthritis Rheum. 2005;52(4):1020-1030.[33] Catrina AI, Trollmo C, af Klint E,et al.Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report.Arthritis Rheum. 2005;52(1):61-72.[34] Takasaki W, Kajino Y, Kajino K,et al.Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor.Nat Biotechnol. 1997; 15(12): 1266-1270.[35] Aoki K, Saito H, Itzstein C,et al.A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss.J Clin Invest. 2006;116(6):1525-1534.[36] Redlich K, Görtz B, Hayer S,et al.Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis.Am J Pathol. 2004;164(2):543-555.[37] Saidenberg-Kermanac'h N, Corrado A, Lemeiter D,et al. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis.Bone. 2004;35(5): 1200-1207.[38] Seriolo B, Paolino S, Sulli A,et al.Are there any positive effects of TNF-alpha blockers on bone metabolism. Reumatismo. 2006;58(3):199-205.[39] Anandarajah AP, Ory P, Salonen D,et al.Effect of adalimumab on joint disease: features of patients with psoriatic arthritis detected by magnetic resonance imaging.Ann Rheum Dis. 2010;69(1):206-209. [40] Musacchio E, Valvason C, Botsios C,et al.The tumor necrosis factor-{alpha}-blocking agent infliximab inhibits interleukin 1beta (IL-1beta) and IL-6 gene expression in human osteoblastic cells.J Rheumatol. 2009;36(8):1575-1579. |
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