IL-17与RANKL/RANK/OPG通路在类风湿性关节炎发病机制中的研究进展
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摘要
类风湿关节炎(rheum atoid arthritis RA)是一种伴随滑膜持续炎症和关节软骨及骨破坏的慢性自身免疫性疾病,其发病机制与多种细胞因子有着密切的关系。白细胞介素-17(IL-17或IL-17A)是由T辅助(Th)17细胞产生的多效性细胞因子,参与包括类风湿关节在内的各种自身免疫和炎性疾病的发病机理。IL-17在RA发病中的重要作用越来越受重视。IL-17对类风湿关节炎中炎症及关节软骨和骨破坏的影响,可通过调节RANKL/RANK/OPG信号通路实现,也可直接刺激破骨细胞前体分化为破骨细胞实现,继而对类风湿关节炎的发生发展产生重要影响,本文主要综述目前IL-17和RANKL/RANK/OPG通路与类风湿性关节炎的相关性研究。
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with persistent inflammation of the synovium and destruction of articular cartilage and bone. Its pathogenesis is closely related to various cytokines. Interleukin-17 (IL-17 or IL-17A) is a pleiotropic cytokine produced by T-assisted (Th) 17 cells and is involved in the pathogenesis of various autoimmune and inflammatory diseases including rheumatoid arthritis. The important role of IL-17 in the pathogenesis of RA is receiving more and more attention. The effect of IL-17 on inflammation and articular cartilage and bone destruction in rheumatoid arthritis can be achieved by regulating the RANKL/RANK/OPG signaling pathway, or directly stimulating the differentiation of osteoclast precursors into osteoclasts, and then The occurrence and development of rheumatoid arthritis has an important impact. This article mainly reviews the current correlation between IL-17 and RANKL/RANK/OPG pathway and rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with persistent inflammation of the synovium and destruction of articular cartilage and bone. Its pathogenesis is closely related to various cytokines. Interleukin-17 (IL-17 or IL-17A) is a pleiotropic cytokine produced by T-assisted (Th) 17 cells and is involved in the pathogenesis of various autoimmune and inflammatory diseases including rheumatoid arthritis. The important role of IL-17 in the pathogenesis of RA is receiving more and more attention. The effect of IL-17 on inflammation and articular cartilage and bone destruction in rheumatoid arthritis can be achieved by regulating the RANKL/RANK/OPG signaling pathway, or directly stimulating the differentiation of osteoclast precursors into osteoclasts, and then The occurrence and development of rheumatoid arthritis has an important impact. This article mainly reviews the current correlation between IL-17 and RANKL/RANK/OPG pathway and rheumatoid arthritis.
引文
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[21]Kartsogiannis V,Zhou H,Horwood NJ,et al.Localization of Rankl(receptor Activator of Nf Kappa B Ligand)Mrna and Protein in Skeletal and Extraskeletal Tissues[J].Bone,1999,25(5):525-534.
[22]Kong YY,Yoshida H,Sarosi I,et al.Opgl Is a Key Regulator of Osteoclastogenesis,Lymphocyte Development and Lymph-node Organogenesis[J].Nature,1999,397(6717):315-323.
[23]Hsu H,Lacey DL,Dunstan CR,et al.Tumor Necrosis Factor Receptor Family Member Rank Mediates Osteoclast Differentiation and Activation Induced By Osteoprotegerin Ligand[J].Proceedings of the National Academy of Sciences of the United States of America,1999,96(7):3540-3545.
[24]Anderson DM,Maraskovsky E,Billingsley WL,et al.A Homologue of the Tnf Receptor and Its Ligand Enhance T-cell Growth and Dendritic-cell Function[J].Nature,1997,390(6656):175-179.
[25]Simonet WS,Lacey DL,Dunstan CR,et al.Osteoprotegerin:a Novel Secreted Protein Involved in the Regulation of Bone Density[J].Cell,1997,89(2):19-309.
[26]Bucay N,Sarosi I,Dunstan CR,et al.Osteoprotegerin-deficient Mice Develop Early Onset Osteoporosis and Arterial calcification[J].Genes Dev,1998,12(9):1260.
[27]Whyte MP,Obrecht SE,Finnegan PM,et al.Osteoprotegerin Deficiency and Juvenile Paget’s Disease[J].N Engl J Med,2002,347(3):175-184.
[28]Hairulislam M I,Saravanan S,Thirugnanasambantham K,et al.Swertiamarin,a natural steroid,prevent bone erosion by modulating RANKL/RANK/OPG signaling[J].International Immunopharmacology,2017,53:114.
[29]Wu Q,Xiong X,Zhang X,et al.Secondary osteoporosis in collagen-induced arthritis rats[J].Journal of Bone&Mineral Metabolism,2016(5):1-17.
[30]刘瑞霞,崔婷,宋冬明,等.类风湿关节炎患者骨代谢相关基因表达及信号通路的变化[J].江苏大学学报(医学版),2016(4):328-332.
[31]Hensvold AH,Joshua V,Li W,et al.Serum Rankl Levels Associate with AntiCitrullinated Protein Antibodies in Early Untreated Rheumatoid Arthritis and Are Modulated Following Methotrexate[J].Arthritis Research&Therapy,2015,17(1):239.
[32]Gaffen SL.Role of Il-17 in the Pathogenesis of Rheumatoid Arthritis[J].Current Rheumatology Reports,2009,11(5):365.
[33]Yago T,Nanke Y,Ichikawa N,et al.Il‐17 Induces Osteoclastogenesis From Human Monocytes Alone in the Absence of Osteoblasts,Which Is Potently Inhibited By Anti‐tnf‐αAntibody:a Novel Mechanism of Osteoclastogenesis By Il‐17[J].Journal of Cellular Biochemistry,2009,108(4):947-955.
[34]Nakano Y,Yamaguchi M,Shimizu M,et al.Interleukin-17 Is Involved in Orthodontically Induced Inflammatory Root Resorption in Dental Pulp Cells[J].American Journal of Orthodontics&Dentofacial Orthopedics,2015,148(2):302-309.
[35]Lin D,Li L,Sun Y,et al.Interleukin-17 Regulates the Expressions of Rankl and Opg in Human Periodontal Ligament Cells Via Traf6/tbk1-jnk/nfkappa B Pathways[J].Immunology,2015,144(3):472-485.
[36]Ganesan R,Rasool M.Interleukin 17 Regulates Shp-2 and Il-17ra/stat-3 Dependent Cyr61,Il-23 and Gm-csf Expression and Rankl Mediated Osteoclastogenesis By Fibroblast-like Synoviocytes in Rheumatoid Arthritis[J].Molecular Immunology,2017,91:134-144.
[37]Nakae S,Nambu A,Sudo K,et al.Suppression of Immune Induction of Collagen-induced Arthritis in Il-17-deficient Mice[J].Journal of Immunology,2003,171(11):6173-6177.
[38]Koenders MI,Marijnissen RJ,Devesa I,et al.Tumor Necrosis Factorinterleukin-17 Interplay Induces S100a8,Interleukin-1β,and Matrix Metalloproteinases,and Drives Irreversible Cartilage Destruction in Murine Arthritis:Rationale for Combination Treatment During Arthritis[J].Arthritis Rheum,2011,63(8):2329-2339.
[39]Shui XL,Lin W,Mao CW,et al.Blockade of Il-17 Alleviated Inflammation in Rat Arthritis and Mmp-13 Expression[J].European Review for Medical&Pharmacological Sciences,2017,21(10):2329.
[40]Koenders MI,Berg WBVD.Secukinumab for Rheumatology:Development and Its Potential Place in Therapy[J].Drug Design Development&Therapy,2016,10(1):2069-2080.
[41]Genovese MC,Durez P,Richards HB,et al.Efficacy and Safety of Secukinumab in Patients with Rheumatoid Arthritis:a Phase Ii,Dosefinding,Double-blind,Randomised,Placebo Controlled Study[J].Annals of Rheumatic Diseases,2013,72(6):863.
[2]Hueber AJ,Asquith DL,Miller AM,et al.Mast Cells Express Il-17a in Rheumatoid Arthritis Synovium[J].Journal of Immunology,2010,184(7):3336-3340.
[3]Uhlig HH,Mckenzie BS,Thompson C,et al.Differential Activity of Il-12 and Il-23 in Mucosal and Systemic Innate Immune Pathology[J].Immunity,2006,25(2):309-318.
[4]Miossec P,Kolls JK.Targeting Il-17 and Th17 Cells in Chronic Inflammation[J].Nature Reviews Drug Discovery,2012,11(10):763-776.
[5]Liang SC,Long AJ,Bennett F,et al.An Il-17f/a Heterodimer Protein Is Produced By Mouse Th17 Cells and Induces Airway Neutrophil Recruitment[J].Journal of Immunology,2007,179(11):7791-7799.
[6]Toh ML,Miossec P.The Role of T Cells in Rheumatoid Arthritis:New Subsets and New Targets[J].Current Opinion in Rheumatology,2007,19(3):284-288.
[7]Lubberts E,Joosten LA,Oppers B,et al.Il-1-independent Role of Il-17 in Synovial Inflammation and Joint Destruction During Collagen-induced Arthritis[J].Journal of Immunology,2001,167(2):1004-1013.
[8]Ju JH,Cho ML,Jhun JY,et al.Oral Administration of Type-ii Collagen Suppresses Il-17-associated Rankl Expression of Cd4+T Cells in Collageninduced Arthritis[J].Immunology Letters,2008,117(1):16-25.
[9]Shui XL,Lin W,Mao CW,et al.Blockade of Il-17 Alleviated Inflammation in Rat Arthritis and Mmp-13 Expression[J].European Review for Medical&Pharmacological Sciences,2017,21(10):2329.
[10]Moon YM,Yoon BY,Her YM,et al.Il-32 and Il-17 Interact and Have the Potential to Aggravate Osteoclastogenesis in Rheumatoid Arthritis[J].Arthritis Research&Therapy,14,6(2012-11-13),2012,14(6):0-0.
[11]Hamburg JPV,Corneth OBJ,Paulissen SMJ,et al.Il-17/th17 Mediated Synovial Inflammation Is Il-22 Independent[J].Annals of the Rheumatic Diseases,2013,72(10):1700-1707.
[12]Fischer JA,Hueber AJ,Wilson S,et al.Combined Inhibition of Tumor Necrosis Factorαand Interleukin-17 as a Therapeutic Opportunity in Rheumatoid Arthritis:Development and Characterization of a Novel Bispecific Antibody[J].Arthritis&Rheumatology,2015,67(1):51.
[13]Gravallese EM,Goldring SR.Cellular Mechanisms and the Role of Cytokines in Bone Erosions in Rheumatoid Arthritis[J].Arthritis&Rheumatology,2000,43(10):2143-2151.
[14]Kanichiro K,Naoyuki T,Eijiro J,et al.Tumor Necrosis FactorαStimulates Osteoclast Differentiation By a Mechanism Independent of the opg/ranklrank Interaction[J].Journal of Experimental Medicine,2000,191(2):275-286.
[15]Koenders MI,Kolls JK,Opperswalgreen B,et al.Interleukin-17 Receptor Deficiency Results in Impaired Synovial Expression of Interleukin-1 and Matrix Metalloproteinases 3,9,and 13 and Prevents Cartilage Destruction During Chronic Reactivated Streptococcal Cell Wall-induced Arthritis[J].Arthritis&Rheumatology,2005,52(10):3239.
[16]Koenders MI,Lubberts E,Fa VDL,et al.Interleukin-17 Acts Independently of Tnf-alpha Under Arthritic Conditions[J].Journal of Immunology,2006,176(10):6262-6269.
[17]Chan KM.Three Is Better Than One:Pre-ligand Receptor Assembly in the Regulation of Tnf Receptor Signaling[J].Cytokine,2007,37(2):101-107.
[18]Lubberts E,Joosten LA,Oppers B,et al.Il-1-independent Role of Il-17 in Synovial Inflammation and Joint Destruction During Collagen-induced Arthritis[J].Journal of Immunology,2001,167(2):13-1004.
[19]Wong BR,Josien R,Lee SY,et al.Trance(tumor Necrosis Factor[tnf]-related Activation-induced Cytokine),a New Tnf Family Member Predominantly Expressed in T Cells,Is a Dendritic Cell-specific Survival Factor[J].Journal of Experimental Medicine,1997,186(12):80-2075.
[20]Silva I,Branco JC.Rank/rankl/opg:Literature Review[J].Acta Reumatológica Portuguesa,2011,36(3):209.
[21]Kartsogiannis V,Zhou H,Horwood NJ,et al.Localization of Rankl(receptor Activator of Nf Kappa B Ligand)Mrna and Protein in Skeletal and Extraskeletal Tissues[J].Bone,1999,25(5):525-534.
[22]Kong YY,Yoshida H,Sarosi I,et al.Opgl Is a Key Regulator of Osteoclastogenesis,Lymphocyte Development and Lymph-node Organogenesis[J].Nature,1999,397(6717):315-323.
[23]Hsu H,Lacey DL,Dunstan CR,et al.Tumor Necrosis Factor Receptor Family Member Rank Mediates Osteoclast Differentiation and Activation Induced By Osteoprotegerin Ligand[J].Proceedings of the National Academy of Sciences of the United States of America,1999,96(7):3540-3545.
[24]Anderson DM,Maraskovsky E,Billingsley WL,et al.A Homologue of the Tnf Receptor and Its Ligand Enhance T-cell Growth and Dendritic-cell Function[J].Nature,1997,390(6656):175-179.
[25]Simonet WS,Lacey DL,Dunstan CR,et al.Osteoprotegerin:a Novel Secreted Protein Involved in the Regulation of Bone Density[J].Cell,1997,89(2):19-309.
[26]Bucay N,Sarosi I,Dunstan CR,et al.Osteoprotegerin-deficient Mice Develop Early Onset Osteoporosis and Arterial calcification[J].Genes Dev,1998,12(9):1260.
[27]Whyte MP,Obrecht SE,Finnegan PM,et al.Osteoprotegerin Deficiency and Juvenile Paget’s Disease[J].N Engl J Med,2002,347(3):175-184.
[28]Hairulislam M I,Saravanan S,Thirugnanasambantham K,et al.Swertiamarin,a natural steroid,prevent bone erosion by modulating RANKL/RANK/OPG signaling[J].International Immunopharmacology,2017,53:114.
[29]Wu Q,Xiong X,Zhang X,et al.Secondary osteoporosis in collagen-induced arthritis rats[J].Journal of Bone&Mineral Metabolism,2016(5):1-17.
[30]刘瑞霞,崔婷,宋冬明,等.类风湿关节炎患者骨代谢相关基因表达及信号通路的变化[J].江苏大学学报(医学版),2016(4):328-332.
[31]Hensvold AH,Joshua V,Li W,et al.Serum Rankl Levels Associate with AntiCitrullinated Protein Antibodies in Early Untreated Rheumatoid Arthritis and Are Modulated Following Methotrexate[J].Arthritis Research&Therapy,2015,17(1):239.
[32]Gaffen SL.Role of Il-17 in the Pathogenesis of Rheumatoid Arthritis[J].Current Rheumatology Reports,2009,11(5):365.
[33]Yago T,Nanke Y,Ichikawa N,et al.Il‐17 Induces Osteoclastogenesis From Human Monocytes Alone in the Absence of Osteoblasts,Which Is Potently Inhibited By Anti‐tnf‐αAntibody:a Novel Mechanism of Osteoclastogenesis By Il‐17[J].Journal of Cellular Biochemistry,2009,108(4):947-955.
[34]Nakano Y,Yamaguchi M,Shimizu M,et al.Interleukin-17 Is Involved in Orthodontically Induced Inflammatory Root Resorption in Dental Pulp Cells[J].American Journal of Orthodontics&Dentofacial Orthopedics,2015,148(2):302-309.
[35]Lin D,Li L,Sun Y,et al.Interleukin-17 Regulates the Expressions of Rankl and Opg in Human Periodontal Ligament Cells Via Traf6/tbk1-jnk/nfkappa B Pathways[J].Immunology,2015,144(3):472-485.
[36]Ganesan R,Rasool M.Interleukin 17 Regulates Shp-2 and Il-17ra/stat-3 Dependent Cyr61,Il-23 and Gm-csf Expression and Rankl Mediated Osteoclastogenesis By Fibroblast-like Synoviocytes in Rheumatoid Arthritis[J].Molecular Immunology,2017,91:134-144.
[37]Nakae S,Nambu A,Sudo K,et al.Suppression of Immune Induction of Collagen-induced Arthritis in Il-17-deficient Mice[J].Journal of Immunology,2003,171(11):6173-6177.
[38]Koenders MI,Marijnissen RJ,Devesa I,et al.Tumor Necrosis Factorinterleukin-17 Interplay Induces S100a8,Interleukin-1β,and Matrix Metalloproteinases,and Drives Irreversible Cartilage Destruction in Murine Arthritis:Rationale for Combination Treatment During Arthritis[J].Arthritis Rheum,2011,63(8):2329-2339.
[39]Shui XL,Lin W,Mao CW,et al.Blockade of Il-17 Alleviated Inflammation in Rat Arthritis and Mmp-13 Expression[J].European Review for Medical&Pharmacological Sciences,2017,21(10):2329.
[40]Koenders MI,Berg WBVD.Secukinumab for Rheumatology:Development and Its Potential Place in Therapy[J].Drug Design Development&Therapy,2016,10(1):2069-2080.
[41]Genovese MC,Durez P,Richards HB,et al.Efficacy and Safety of Secukinumab in Patients with Rheumatoid Arthritis:a Phase Ii,Dosefinding,Double-blind,Randomised,Placebo Controlled Study[J].Annals of Rheumatic Diseases,2013,72(6):863.