椎间盘退变分子生物学机制及再生治疗的优势与未来
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摘要
背景:多因素引起的椎间盘退行性病变所导致的严重的腰背痛是致残率最高的脊柱疾病,随着医学分子生物学的发展及椎间盘退变机制研究的深入,椎间盘退变的再生疗法为恢复这种难治性疾病提够了可能。目的:文章对近年来国内外各研究者关于椎间盘退变的相关分子和各种再生疗法在椎间盘退变中应用的研究进行归纳总结。方法:使用计算机检索Pub Med、Embase、Web of science数据库和中国知网、万方、维普数据库在1995年1月至2019年3月发表的关于椎间盘退变再生治疗的相关文献,其中中文的检索关键词包括"椎间盘退变、腰背痛、再生治疗、生长因子、细胞治疗、基因治疗、病毒载体、非病毒载体",英文的关键词为"Intervertebral disc degeneration,low back pain,regenerative therapy,growth factor,cell therapy;gene therapy,viral vector,non-viral vector",筛选出相关文献后再进一步归纳总结。结果与结论:研究显示,近20多种基因影响着髓核细胞的变性,其中就包括各种非编码RNA(如micro RNA、linc RNA和lnc RNA)。目前,生长因子疗法、细胞疗法和基因疗法等再生研究已经取得了预期效果。非病毒载体转导的基因治疗能避免感染的风险和靶细胞突变的可能,将成为恢复或缓解椎间盘退变的强大工具,具用广阔的应用前景。然而,这些再生疗法也有一定的局限性,在其应用于临床之前,需进行大量的基础研究和临床实验,以便评估其疗效和对逆转退变的影响。
BACKGROUND: Severe low back pain caused by multi-factor disc degeneration is the most disabling spinal disease. However, existing treatments cannot cure this painful disease. Fortunately, with the development of medical molecular biology and the in-depth study of the mechanism of intervertebral disc degeneration, the regenerative therapy of intervertebral disc degeneration is possible to cure this refractory disease.OBJECTIVE: To summarize the researches on the related molecules of intervertebral disc degeneration and the application of various regenerative therapies in intervertebral disc degeneration in recent years.METHODS: A computer based online search of Pub Med, Embase, Web of science, CNKI, Wanfang, VIP databases for related literature on the treatment of intervertebral disc degeneration and regeneration published during January 1995 to March 2019 using the search terms "intervertebral disc degeneration, low back pain, regenerative therapy, growth factor, cell therapy, gene therapy, viral vector, non-viral vector" in Chinese and English. The related literatures were included in the final analysis.RESULTS AND CONCLUSION: Studies have shown that nearly 20 genes affect the degeneration of nucleus pulposus cells, including various non-coding RNAs(such as micro RNA, linc RNA and lnc RNA). Currently, regeneration studies such as growth factor therapy, cell therapy, and gene therapy have achieved the desired results. Non-viral vector-transduced gene therapy can avoid the risk of infection and the possibility of target cell mutation, and will become a powerful tool for restoring or relieving disc degeneration, and has broad application prospects. However, these regenerative therapies also have certain limitations. Before they are applied to the clinic, a large number of basic and clinical experiments are needed to evaluate their efficacy and the effects on reversing degeneration.
BACKGROUND: Severe low back pain caused by multi-factor disc degeneration is the most disabling spinal disease. However, existing treatments cannot cure this painful disease. Fortunately, with the development of medical molecular biology and the in-depth study of the mechanism of intervertebral disc degeneration, the regenerative therapy of intervertebral disc degeneration is possible to cure this refractory disease.OBJECTIVE: To summarize the researches on the related molecules of intervertebral disc degeneration and the application of various regenerative therapies in intervertebral disc degeneration in recent years.METHODS: A computer based online search of Pub Med, Embase, Web of science, CNKI, Wanfang, VIP databases for related literature on the treatment of intervertebral disc degeneration and regeneration published during January 1995 to March 2019 using the search terms "intervertebral disc degeneration, low back pain, regenerative therapy, growth factor, cell therapy, gene therapy, viral vector, non-viral vector" in Chinese and English. The related literatures were included in the final analysis.RESULTS AND CONCLUSION: Studies have shown that nearly 20 genes affect the degeneration of nucleus pulposus cells, including various non-coding RNAs(such as micro RNA, linc RNA and lnc RNA). Currently, regeneration studies such as growth factor therapy, cell therapy, and gene therapy have achieved the desired results. Non-viral vector-transduced gene therapy can avoid the risk of infection and the possibility of target cell mutation, and will become a powerful tool for restoring or relieving disc degeneration, and has broad application prospects. However, these regenerative therapies also have certain limitations. Before they are applied to the clinic, a large number of basic and clinical experiments are needed to evaluate their efficacy and the effects on reversing degeneration.
引文
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[36] Shen L, Wu Y, Han L, et al. Overexpression of growth and differentiation factor-5 inhibits inflammatory factors released by intervertebral disc cells. Exp Ther Med. 2018;15(4):3603-3608.
[37] Zhu J, Xia K, Yu W, et al. Sustained release of GDF5 from a designed coacervate attenuates disc degeneration in a rat model. Acta Biomater. 2019;86:300-311.
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[40] Chakravarthy K, Chen Y, He C, et al. Stem cell therapy for chronic pain management:review of uses, advances, and adverse effects. Pain Physician. 2017;20(4):293-305.
[41] Nukaga T, Sakai D, Tanaka M, et al. Transplantation of activated nucleus pulposus cells after cryopreservation:efficacy study in a canine disc degeneration model. Eur Cells Mater. 2016;31:95-106.
[42] Gantenbein B, Calandriello E, Wuertz-Kozak K, et al.Activation of intervertebral disc cells by co-culture with notochordal cells, conditioned medium and hypoxia. BMC Musculoskelet Disord. 2014;15:422-436.
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[44] Xia K, Gong Z, Zhu J, et al. Differentiation of pluripotent stem cells into nucleus pulposus progenitor cells for intervertebral disc regeneration. Curr Stem Cell Res Ther. 2019;14(1):57-64.
[45] Yoshikawa T, Ueda Y, Miyazaki K, et al. Disc regeneration therapy using marrow mesenchymal cell transplantation:a report of two case studies. Spine. 2010;35(11):E475-E480.
[46] Kraus P, Lufkin T. Implications for a stem cell regenerative medicine based approach to human intervertebral disk degeneration. Front Cell Dev Biol. 2017;5:17-22.
[47] Noriega DC, Ardura F, Hernandez-Ramajo R, et al.Intervertebral disc repair by allogeneic mesenchymal bone marrow cells:a randomized controlled trial. Transplantation.2017;101(8):1945-1951.
[48] Fernandez-Moure J, Moore CA, Kim K, et al. Novel therapeutic strategies for degenerative disc disease:Review of cell biology and intervertebral disc cell therapy. SAGE Open Med. 2018;6:2050312118761674.
[49] Mayer JE, Iatridis JC, Chan D, et al. Genetic polymorphisms associated with intervertebral disc degeneration. Spine J.2013;13(3):299-317.
[50] Yue B, Lin Y, Ma X, et al. Effect of Survivin gene therapy via lentivirus vector on the course of intervertebral disc degeneration in an in vivo rabbit model. Mol Med Rep.2016;14(5):4593-4598.
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[52] Wehling P, Schulitz KP, Robbins PD, et al. Transfer of genes to chondrocytic cells of the lumbar spine. Proposal for a treatment strategy of spinal disorders by local gene therapy.Spine. 1997;22(10):1092-1097.
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[2] Schol J, Sakai D. Cell therapy for intervertebral disc herniation and degenerative disc disease:clinical trials. Int Orthop. 2019;43(3):1011-1025.
[3] Liu Y, Yu T, Ma XX, et al. Lentivirus-mediated TGF-beta3,CTGF and TIMP1 gene transduction as a gene therapy for intervertebral disc degeneration in an in vivo rabbit model.Exp Ther Med. 2016;11(4):1399-1404.
[4] Navone SE, Marfia G, Giannoni A, et al. Inflammatory mediators and signalling pathways controlling intervertebral disc degeneration. Histol Histopathol. 2017;32(6):523-542.
[5] Anitua E, Padilla S. Biologic therapies to enhance intervertebral disc repair. Regen Med. 2018;13(1):55-72.
[6] Lawson LY, Harfe BD. Developmental mechanisms of intervertebral disc and vertebral column formation. Wiley Interdiscip Rev Dev Biol. 2017;6(6):e283-e296.
[7] Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013;369(5):448-457.
[8] Hemanta D, Jiang XX, Feng ZZ, et al. Etiology for degenerative disc disease. Chin Med Sci J. 2016;31(3):185-191.
[9] Ouyang ZH, Wang WJ, Yan YG, et al. The PI3K/Akt pathway:a critical player in intervertebral disc degeneration.Oncotarget. 2017;8(34):57870-57881.
[10] Wang C, Wang W, Yang W, et al. Micro RNAs:a type of novel regulative factor for intervertebral disc degeneration. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2016;45(2):170-178.
[11] Stergar J, Gradisnik L, Velnar T, et al. Intervertebral disc tissue engineering:a brief review. Bosn J Basic Med Sci.2019;19(2):130-137.
[12] Helm Ii S, Simopoulos TT, Stojanovic M, et al. Effectiveness of thermal annular procedures in treating discogenic low back pain. Pain Physician. 2017;20(6):447-470.
[13] Frost BA, Camarero-Espinosa S, Foster EJ. Materials for the spine:anatomy, problems, and solutions. Materials(Basel).2019;12(2):253-293.
[14] Donnally IC, Varacallo M. Lumbosacral Disc Injuries.Stat Pearls. Treasure Island(FL). Stat Pearls[Internet].Treasure Island(FL):Stat Pearls Publishing; 2019.
[15] Feng C, Liu H, Yang M, et al. Disc cell senescence in intervertebral disc degeneration:Causes and molecular pathways. Cell Cycle. 2016;15(13):1674-1684.
[16] Vo NV, Hartman RA, Patil PR, et al. Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res. 2016;34(8):1289-1306.
[17] Blanquer SB, Grijpma DW, Poot AA. Delivery systems for the treatment of degenerated intervertebral discs. Adv Drug Deliv Rev. 2015;84:172-187.
[18] Bowles RD, Setton LA. Biomaterials for intervertebral disc regeneration and repair. Biomaterials. 2017;129:54-67.
[19] Johnson ZI, Schoepflin ZR, Choi H, et al. Disc in flames:Roles of TNF-alpha and IL-1beta in intervertebral disc degeneration. Eur Cells Mater. 2015;30:104-117.
[20] Vadala G, Russo F, Ambrosio L, et al. Stem cells sources for intervertebral disc regeneration. World J Stem Cells. 2016;8(5):185-201.
[21] Smith LJ, Silverman L, Sakai D, et al. Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic:Recommendations of the ORS spine section. JOR Spine, 2018;1(4):e1036-e1049.
[22] Sampara P, Banala RR, Vemuri SK, et al. Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration:a review.Gene Ther. 2018;25(2):67-82.
[23] Basso M, Cavagnaro L, Zanirato A, et al. What is the clinical evidence on regenerative medicine in intervertebral disc degeneration? Musculoskeletal Surg. 2017;101(2):93-104.
[24] Dowdell J, Erwin M, Choma T, et al. Intervertebral Disk Degeneration and Repair. Neurosurgery. 2017;80(3S):S46-S54.
[25] Sun Y, Leung VY, Cheung KM. Clinical trials of intervertebral disc regeneration:current status and future developments. Int Orthop. 2019;43(4):1003-1010.
[26] Kennon J C, Awad ME, Chutkan N, et al. Current insights on use of growth factors as therapy for Intervertebral Disc Degeneration. Biomol Concepts. 2018;9(1):43-52.
[27] Tan Y, Yao X, Dai Z, et al. Bone morphogenetic protein 2alleviated intervertebral disc degeneration through mediating the degradation of ECM and apoptosis of nucleus pulposus cells via the PI3K/Akt pathway. Int J Mol Med. 2019;43(1):583-592.
[28] Yang W, Yu XH, Wang C, et al. Interleukin-1beta in intervertebral disk degeneration. Clinica Chim Acta. 2015;450:262-272.
[29] Li P, Zhang R, Gan Y, et al. Effects of osteogenic protein-1 on intervertebral disc regeneration:a systematic review of animal studies. Biomed Pharmacother. 2017;88:260-266.
[30] Wang SZ, Chang Q, Lu J, et al. Growth factors and platelet-rich plasma:promising biological strategies for early intervertebral disc degeneration. Int Orthop. 2015;39(5):927-934.
[31] Jia J, Wang SZ, Ma LY, et al. The differential effects of leukocyte-containing and pure platelet-rich plasma on nucleus pulposus-derived mesenchymal stem cells:implications for the clinical treatment of intervertebral disc degeneration. Stem Cells Int. 2018;2018:7162084.
[32] Gelalis ID, Christoforou G, Charchanti A, et al. Autologous platelet-rich plasma(PRP)effect on intervertebral disc restoration:an experimental rabbit model. Eur J Orthop Surg Traumatol. 2019;29(3):545-551.
[33] Akeda K, Yamada J, Linn ET, et al. Platelet-rich plasma in the management of chronic low back pain:a critical review. J Pain Res. 2019;12:753-767.
[34] Feng C, Liu H, Yang Y, et al. Growth and differentiation factor-5 contributes to the structural and functional maintenance of the intervertebral disc. Cell Physiol Biochem.2015;35(1):1-16.
[35] Tran CM, Shapiro IM, Risbud MV. Molecular regulation of CCN2 in the intervertebral disc:lessons learned from other connective tissues. Matrix Biol. 2013;32(6):298-306.
[36] Shen L, Wu Y, Han L, et al. Overexpression of growth and differentiation factor-5 inhibits inflammatory factors released by intervertebral disc cells. Exp Ther Med. 2018;15(4):3603-3608.
[37] Zhu J, Xia K, Yu W, et al. Sustained release of GDF5 from a designed coacervate attenuates disc degeneration in a rat model. Acta Biomater. 2019;86:300-311.
[38] Sakai D, Schol J. Cell therapy for intervertebral disc repair:clinical perspective. J Orthop Translat. 2017;9:8-18.
[39] Vasiliadis ES, Pneumaticos SG, Evangelopoulos DS, et al.Biologic treatment of mild and moderate intervertebral disc degeneration. Mol Med. 2014;20:400-409.
[40] Chakravarthy K, Chen Y, He C, et al. Stem cell therapy for chronic pain management:review of uses, advances, and adverse effects. Pain Physician. 2017;20(4):293-305.
[41] Nukaga T, Sakai D, Tanaka M, et al. Transplantation of activated nucleus pulposus cells after cryopreservation:efficacy study in a canine disc degeneration model. Eur Cells Mater. 2016;31:95-106.
[42] Gantenbein B, Calandriello E, Wuertz-Kozak K, et al.Activation of intervertebral disc cells by co-culture with notochordal cells, conditioned medium and hypoxia. BMC Musculoskelet Disord. 2014;15:422-436.
[43] Mochida J, Sakai D, Nakamura Y, et al. Intervertebral disc repair with activated nucleus pulposus cell transplantation:a three-year, prospective clinical study of its safety. Eur Cells Mater. 2015;29:202-212.
[44] Xia K, Gong Z, Zhu J, et al. Differentiation of pluripotent stem cells into nucleus pulposus progenitor cells for intervertebral disc regeneration. Curr Stem Cell Res Ther. 2019;14(1):57-64.
[45] Yoshikawa T, Ueda Y, Miyazaki K, et al. Disc regeneration therapy using marrow mesenchymal cell transplantation:a report of two case studies. Spine. 2010;35(11):E475-E480.
[46] Kraus P, Lufkin T. Implications for a stem cell regenerative medicine based approach to human intervertebral disk degeneration. Front Cell Dev Biol. 2017;5:17-22.
[47] Noriega DC, Ardura F, Hernandez-Ramajo R, et al.Intervertebral disc repair by allogeneic mesenchymal bone marrow cells:a randomized controlled trial. Transplantation.2017;101(8):1945-1951.
[48] Fernandez-Moure J, Moore CA, Kim K, et al. Novel therapeutic strategies for degenerative disc disease:Review of cell biology and intervertebral disc cell therapy. SAGE Open Med. 2018;6:2050312118761674.
[49] Mayer JE, Iatridis JC, Chan D, et al. Genetic polymorphisms associated with intervertebral disc degeneration. Spine J.2013;13(3):299-317.
[50] Yue B, Lin Y, Ma X, et al. Effect of Survivin gene therapy via lentivirus vector on the course of intervertebral disc degeneration in an in vivo rabbit model. Mol Med Rep.2016;14(5):4593-4598.
[51] Smith E, Blomberg P. Gene therapy-from idea to reality.Lakartidningen. 2017;114:EWYL.
[52] Wehling P, Schulitz KP, Robbins PD, et al. Transfer of genes to chondrocytic cells of the lumbar spine. Proposal for a treatment strategy of spinal disorders by local gene therapy.Spine. 1997;22(10):1092-1097.
[53] Zhang YH, Zhao YL, Li B, et al. Lentivirus is an efficient and stable transduction vector for intervertebral disc cells. World Neurosurg. 2018;111:e348-e354.
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