Research progress of mitogen activation protein kinase signaling pathway in rheumatoid arthritis_West China Medical Journal

Authors：

XIAO Zhuoran ¹ , ZHANG Haiping ¹ , HE Yufang ¹ , PAN Xuan ¹ , ZHENG Enping ¹ , CHEN Bing ² , YU Changxi ^2,3 ,  YANG Jian ^2,3

1. The Third Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350000, P. R. China;
2. School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350000, P. R. China;
3. Fujian Key Laboratory of Natural Medicine Pharmacology, Fuzhou, Fujian 350000, P. R. China;

Corresponding author：

YANG Jian, Email: fjmukent@mail.fjmu.edu.cn

Keywords：

Mitogen activation protein kinase; signaling pathway; rheumatoid arthritis

DOI：

10.7507/1002-0179.202011092

Video：

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Rheumatoid arthritis (RA) is a chronic autoimmune disease remarkably characterized by synovitis of joints, whose pathogenesis is complicated and not yet fully elucidated. A variety of cells, cytokines and intercellular signaling pathways are involved in the occurrence and development of RA. The mitogen activation protein kinase (MAPK) signaling pathway is closely related to the pathogenesis of RA, and plays an important role in the formation of pannus, synovitis, and bone destruction. This paper reviews the research progress of MAPK signaling pathway in RA from the aspects of the interaction of MAPK signaling pathway with a variety of key cells and cytokines in the pathogenesis of RA, in order to provide a direction and theoretical basis for anti-RA drug therapy research.

Citation： XIAO Zhuoran, ZHANG Haiping, HE Yufang, PAN Xuan, ZHENG Enping, CHEN Bing, YU Changxi, YANG Jian. Research progress of mitogen activation protein kinase signaling pathway in rheumatoid arthritis. West China Medical Journal, 2022, 37(3): 453-459. doi: 10.7507/1002-0179.202011092 Copy

1.	张彦景, 张建新. MAPK 信号转导通路与类风湿关节炎的研究进展. 河北医药, 2016, 38(17): 2677-2681.
2.	周春燕, 药立波. 生物化学与分子生物学. 北京: 人民卫生出版社, 1978: 327-345.
3.	Rubinfeld H, Seger R. The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol, 2005, 31(2): 151-174.
4.	陈晓俊, 王健英, 金素安, 等. 中药影响类风湿性关节炎信号通路的研究进展. 中华中医药学刊, 2016, 34(7): 1735-1739.
5.	孙明慧, 吴虹, 卜妍红, 等. 介导缺氧诱导因子-1α表达的相关信号通路在类风湿性关节炎中的研究进展. 中国药理学通报, 2019, 35(9): 1197-1202.
6.	韩海燕, 沈敬华. 类风湿关节炎发病机制的研究进展. 世界最新医学信息文摘, 2019, 19(93): 66-67, 69.
7.	Lin YP, Su CC, Huang JY, et al. Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis. Mol Immunol, 2009, 46(16): 3328-3335.
8.	Huang L, Wang M, Yan Y, et al. OX40L induces helper T cell differentiation during cell immunity of asthma through PI3K/AKT and P38 MAPK signaling pathway. J Transl Med, 2018, 16(1): 74.
9.	Chen Y, Li H, Li M, et al. Salvia miltiorrhiza polysaccharide activates T Lymphocytes of cancer patients through activation of TLRs mediated -MAPK and -NF-κB signaling pathways. J Ethnopharmacol, 2017, 200: 165-173.
10.	Jakhar R, Sharma C, Paul S, et al. Immunosuppressive potential of astemizole against LPS activated T cell proliferation and cytokine secretion in RAW macrophages, zebrafish larvae and mouse splenocytes by modulating MAPK signaling pathway. Int Immunopharmacol, 2018, 65: 268-278.
11.	Klebanoff CA, Crompton JG, Leonardi AJ, et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight, 2017, 2(23): e95103.
12.	Azoulay-Alfaguter I, Mor A. Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling. Eur J Immunol, 2018, 48(11): 1915-1917.
13.	Yu Z, Xu H, Wang H, et al. Foxc1 promotes the proliferation of fibroblast-like synoviocytes in rheumatoid arthritis via PI3K/AKT signalling pathway. Tissue Cell, 2018, 53: 15-22.
14.	Ma JD, Jing J, Wang JW, et al. A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther, 2019, 21(1): 153.
15.	牛红青. 基于 JAK2/STAT3 和 p38MAPK 信号通路探讨环磷酰胺联合甲氨蝶呤抑制类风湿关节炎成纤维样滑膜细胞 RANKL 表达的研究. 太原: 山西医科大学, 2018.
16.	王慧莲, 孟庆良, 李松伟, 等. 汉黄芩素通过激活活性氧簇介导的 p38MAPK 信号通路诱导类风湿关节炎成纤维样滑膜细胞凋亡. 中国骨质疏松杂志, 2017, 23(7): 890-895.
17.	罗素. 大黄素对 TNF-α诱导的成纤维样滑膜细胞株 MH7A 细胞 ERK1/2 和 p38MAPK 的影响. 重庆: 重庆医科大学, 2017.
18.	Zhai KF, Duan H, Cui CY, et al. Liquiritin from glycyrrhiza uralensis attenuating rheumatoid arthritis via reducing inflammation, suppressing angiogenesis, and inhibiting MAPK signaling pathway. J Agric Food Chem, 2019, 67(10): 2856-2864.
19.	刘春芳, 何莲花, 王靖霞, 等. 风湿祛痛胶囊对类风湿关节炎滑膜 Akt 和 MAPK 信号通路的影响. 中国实验方剂学杂志, 2019, 25(13): 35-40.
20.	王霞, 蒋礼, 何燕玲, 等. 黑骨藤中咖啡酰基奎宁酸类化合物体外抗类风湿性关节炎机制研究. 中国药理学通报, 2018, 34(10): 1362-1367.
21.	杨敏, 洪梦琴, 范星宇. RANKL-RANK-OPG 信号通路对类风湿关节炎骨破坏作用的研究进展. 医学与哲学, 2018, 39(4): 64-69.
22.	Cong Q, Jia H, Li P, et al. p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner. Sci Rep, 2017, 7: 45964.
23.	Ke D, Zhu Y, Zheng W, et al. Autophagy mediated by JNK1 resists apoptosis through TRAF3 degradation in osteoclastogenesis. Biochimie, 2019, 167: 217-227.
24.	Panagopoulos V, Liapis V, Zinonos I, et al. Peroxidase enzymes inhibit osteoclast differentiation and bone resorption. Mol Cell Endocrinol, 2017, 440: 8-15.
25.	Rantlha M, Sagar T, Kruger MC, et al. Ellagic acid inhibits RANKL-induced osteoclast differentiation by suppressing the p38 MAP kinase pathway. Arch Pharm Res, 2017, 40(1): 79-87.
26.	Kim K, Kim JH, Kim I, et al. Rev-erbα negatively regulates osteoclast and osteoblast differentiation through p38 MAPK signaling pathway. Mol Cells, 2020, 43(1): 34-47.
27.	陈红梅, 王友莲. 破骨细胞在类风湿关节炎致骨破坏病理变化中的作用及其调控. 中国骨质疏松杂志, 2016, 22(9): 1168-1173.
28.	Xu W, Chen X, Wang Y, et al. Chitooligosaccharide inhibits RANKL-induced osteoclastogenesis and ligation-induced periodontitis by suppressing MAPK/ c-fos/NFATC1 signaling. J Cell Physiol, 2020, 235(3): 3022-3032.
29.	Shang W, Zhao LJ, Dong XL, et al. Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways. Mol Med Rep, 2016, 14(4): 3620-3626.
30.	Bustamante MF, Garcia-Carbonell R, Whisenant KD, et al. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther, 2017, 19(1): 110.
31.	Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol, 2016, 12(8): 472-485.
32.	Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev, 2010, 233(1): 233-255.
33.	左芳, 韦婷, 童东, 等. 基于 MAPK 通路研究五味甘露药浴散加减方治疗类风湿关节炎的药效机制. 中国中药杂志, 2017, 42(7): 1245-1250.
34.	罗素, 荣晓凤, 彭菲菲. 大黄素对 TNF-α诱导的成纤维样滑膜细胞株 MH7A 细胞 ERK1/2 和 p38MAPK 的影响. 免疫学杂志, 2017, 33(2): 113-117.
35.	汪荣盛, 刘佳, 童萍, 等. 雷藤舒对 TNF-α诱导的人类风湿关节炎滑膜成纤维细胞促凋亡、抗炎及对 Ras-MAPKs 信号通路的调节作用. 上海中医药大学学报, 2016, 30(3): 82-87.
36.	唐敏. 马钱子碱对 TNF-α诱导人类风湿关节炎成纤维样滑膜细胞的增殖影响和 MAPK 通路中 JNK 调控的研究. 泸州: 泸州医学院, 2014.
37.	Yang Y, Ye Y, Qiu Q, et al. Triptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathway. Int Immunopharmacol, 2016, 41: 8-16.
38.	王亮. 类风湿关节炎免疫治疗药物的作用机制和应用进展. 中国处方药, 2020, 18(4): 25-26.
39.	莫选荣, 谢江文, 吕国菊, 等. TAK1 基因沉默对 TNF-α诱导的滑膜细胞 IL-6、IL-8 表达的影响. 中国应用生理学杂志, 2017, 33(5): 471-475.
40.	唐莼, 李昀, 林小军, 等. 泌乳素促进类风湿关节炎患者外周血单个核细胞分泌白细胞介素-6. 中国病理生理杂志, 2016, 32(11): 2062-2066.
41.	董佳莉. IL-6 调控类风湿关节炎患者外周血淋巴细胞 P-糖蛋白信号转导通路的研究. 太原: 山西医科大学, 2016.
42.	欧阳寻丽, 李寒, 孙晓彤, 等. 白细胞介素-34 对类风湿关节炎成纤维样滑膜细胞 CCL28 表达的影响. 中国免疫学杂志, 2018, 34(2): 239-242.
43.	卫丹丹. 1, 25(OH)₂D₃ 对类风湿关节炎成纤维滑膜细胞 IL-22 介导的 RANKL 蛋白表达的影响. 太原: 山西医科大学, 2016.
44.	Dinesh P, Rasool M. Multifaceted role of IL-21 in rheumatoid arthritis: current understanding and future perspectives. J Cell Physiol, 2018, 233(5): 3918-3928.
45.	王静, 赵庆杰, 卓小斌, 等. 类风湿性关节炎的治疗药物研究进展. 药学实践杂志, 2019, 37(6): 485-490.
46.	Namba S, Nakano R, Kitanaka T, et al. ERK2 and JNK1 contribute to TNF-α-induced IL-8 expression in synovial fibroblasts. PLoS One, 2017, 12(8): e0182923.
47.	商玮. 姜黄素对类风湿关节炎患者 PBMC 破骨细胞生成的影响及可能机制的研究. 南京: 南京中医药大学, 2016.
48.	Huang CC, Chiou CH, Liu SC, et al. Melatonin attenuates TNF-α and IL-1β expression in synovial fibroblasts and diminishes cartilage degradation: implications for the treatment of rheumatoid arthritis. J Pineal Res, 2019, 66(3): e12560.

1. 张彦景, 张建新. MAPK 信号转导通路与类风湿关节炎的研究进展. 河北医药, 2016, 38(17): 2677-2681.
2. 周春燕, 药立波. 生物化学与分子生物学. 北京: 人民卫生出版社, 1978: 327-345.
3. Rubinfeld H, Seger R. The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol, 2005, 31(2): 151-174.
4. 陈晓俊, 王健英, 金素安, 等. 中药影响类风湿性关节炎信号通路的研究进展. 中华中医药学刊, 2016, 34(7): 1735-1739.
5. 孙明慧, 吴虹, 卜妍红, 等. 介导缺氧诱导因子-1α表达的相关信号通路在类风湿性关节炎中的研究进展. 中国药理学通报, 2019, 35(9): 1197-1202.
6. 韩海燕, 沈敬华. 类风湿关节炎发病机制的研究进展. 世界最新医学信息文摘, 2019, 19(93): 66-67, 69.
7. Lin YP, Su CC, Huang JY, et al. Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis. Mol Immunol, 2009, 46(16): 3328-3335.
8. Huang L, Wang M, Yan Y, et al. OX40L induces helper T cell differentiation during cell immunity of asthma through PI3K/AKT and P38 MAPK signaling pathway. J Transl Med, 2018, 16(1): 74.
9. Chen Y, Li H, Li M, et al. Salvia miltiorrhiza polysaccharide activates T Lymphocytes of cancer patients through activation of TLRs mediated -MAPK and -NF-κB signaling pathways. J Ethnopharmacol, 2017, 200: 165-173.
10. Jakhar R, Sharma C, Paul S, et al. Immunosuppressive potential of astemizole against LPS activated T cell proliferation and cytokine secretion in RAW macrophages, zebrafish larvae and mouse splenocytes by modulating MAPK signaling pathway. Int Immunopharmacol, 2018, 65: 268-278.
11. Klebanoff CA, Crompton JG, Leonardi AJ, et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight, 2017, 2(23): e95103.
12. Azoulay-Alfaguter I, Mor A. Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling. Eur J Immunol, 2018, 48(11): 1915-1917.
13. Yu Z, Xu H, Wang H, et al. Foxc1 promotes the proliferation of fibroblast-like synoviocytes in rheumatoid arthritis via PI3K/AKT signalling pathway. Tissue Cell, 2018, 53: 15-22.
14. Ma JD, Jing J, Wang JW, et al. A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther, 2019, 21(1): 153.
15. 牛红青. 基于 JAK2/STAT3 和 p38MAPK 信号通路探讨环磷酰胺联合甲氨蝶呤抑制类风湿关节炎成纤维样滑膜细胞 RANKL 表达的研究. 太原: 山西医科大学, 2018.
16. 王慧莲, 孟庆良, 李松伟, 等. 汉黄芩素通过激活活性氧簇介导的 p38MAPK 信号通路诱导类风湿关节炎成纤维样滑膜细胞凋亡. 中国骨质疏松杂志, 2017, 23(7): 890-895.
17. 罗素. 大黄素对 TNF-α诱导的成纤维样滑膜细胞株 MH7A 细胞 ERK1/2 和 p38MAPK 的影响. 重庆: 重庆医科大学, 2017.
18. Zhai KF, Duan H, Cui CY, et al. Liquiritin from glycyrrhiza uralensis attenuating rheumatoid arthritis via reducing inflammation, suppressing angiogenesis, and inhibiting MAPK signaling pathway. J Agric Food Chem, 2019, 67(10): 2856-2864.
19. 刘春芳, 何莲花, 王靖霞, 等. 风湿祛痛胶囊对类风湿关节炎滑膜 Akt 和 MAPK 信号通路的影响. 中国实验方剂学杂志, 2019, 25(13): 35-40.
20. 王霞, 蒋礼, 何燕玲, 等. 黑骨藤中咖啡酰基奎宁酸类化合物体外抗类风湿性关节炎机制研究. 中国药理学通报, 2018, 34(10): 1362-1367.
21. 杨敏, 洪梦琴, 范星宇. RANKL-RANK-OPG 信号通路对类风湿关节炎骨破坏作用的研究进展. 医学与哲学, 2018, 39(4): 64-69.
22. Cong Q, Jia H, Li P, et al. p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner. Sci Rep, 2017, 7: 45964.
23. Ke D, Zhu Y, Zheng W, et al. Autophagy mediated by JNK1 resists apoptosis through TRAF3 degradation in osteoclastogenesis. Biochimie, 2019, 167: 217-227.
24. Panagopoulos V, Liapis V, Zinonos I, et al. Peroxidase enzymes inhibit osteoclast differentiation and bone resorption. Mol Cell Endocrinol, 2017, 440: 8-15.
25. Rantlha M, Sagar T, Kruger MC, et al. Ellagic acid inhibits RANKL-induced osteoclast differentiation by suppressing the p38 MAP kinase pathway. Arch Pharm Res, 2017, 40(1): 79-87.
26. Kim K, Kim JH, Kim I, et al. Rev-erbα negatively regulates osteoclast and osteoblast differentiation through p38 MAPK signaling pathway. Mol Cells, 2020, 43(1): 34-47.
27. 陈红梅, 王友莲. 破骨细胞在类风湿关节炎致骨破坏病理变化中的作用及其调控. 中国骨质疏松杂志, 2016, 22(9): 1168-1173.
28. Xu W, Chen X, Wang Y, et al. Chitooligosaccharide inhibits RANKL-induced osteoclastogenesis and ligation-induced periodontitis by suppressing MAPK/ c-fos/NFATC1 signaling. J Cell Physiol, 2020, 235(3): 3022-3032.
29. Shang W, Zhao LJ, Dong XL, et al. Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways. Mol Med Rep, 2016, 14(4): 3620-3626.
30. Bustamante MF, Garcia-Carbonell R, Whisenant KD, et al. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther, 2017, 19(1): 110.
31. Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol, 2016, 12(8): 472-485.
32. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev, 2010, 233(1): 233-255.
33. 左芳, 韦婷, 童东, 等. 基于 MAPK 通路研究五味甘露药浴散加减方治疗类风湿关节炎的药效机制. 中国中药杂志, 2017, 42(7): 1245-1250.
34. 罗素, 荣晓凤, 彭菲菲. 大黄素对 TNF-α诱导的成纤维样滑膜细胞株 MH7A 细胞 ERK1/2 和 p38MAPK 的影响. 免疫学杂志, 2017, 33(2): 113-117.
35. 汪荣盛, 刘佳, 童萍, 等. 雷藤舒对 TNF-α诱导的人类风湿关节炎滑膜成纤维细胞促凋亡、抗炎及对 Ras-MAPKs 信号通路的调节作用. 上海中医药大学学报, 2016, 30(3): 82-87.
36. 唐敏. 马钱子碱对 TNF-α诱导人类风湿关节炎成纤维样滑膜细胞的增殖影响和 MAPK 通路中 JNK 调控的研究. 泸州: 泸州医学院, 2014.
37. Yang Y, Ye Y, Qiu Q, et al. Triptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathway. Int Immunopharmacol, 2016, 41: 8-16.
38. 王亮. 类风湿关节炎免疫治疗药物的作用机制和应用进展. 中国处方药, 2020, 18(4): 25-26.
39. 莫选荣, 谢江文, 吕国菊, 等. TAK1 基因沉默对 TNF-α诱导的滑膜细胞 IL-6、IL-8 表达的影响. 中国应用生理学杂志, 2017, 33(5): 471-475.
40. 唐莼, 李昀, 林小军, 等. 泌乳素促进类风湿关节炎患者外周血单个核细胞分泌白细胞介素-6. 中国病理生理杂志, 2016, 32(11): 2062-2066.
41. 董佳莉. IL-6 调控类风湿关节炎患者外周血淋巴细胞 P-糖蛋白信号转导通路的研究. 太原: 山西医科大学, 2016.
42. 欧阳寻丽, 李寒, 孙晓彤, 等. 白细胞介素-34 对类风湿关节炎成纤维样滑膜细胞 CCL28 表达的影响. 中国免疫学杂志, 2018, 34(2): 239-242.
43. 卫丹丹. 1, 25(OH)₂D₃ 对类风湿关节炎成纤维滑膜细胞 IL-22 介导的 RANKL 蛋白表达的影响. 太原: 山西医科大学, 2016.
44. Dinesh P, Rasool M. Multifaceted role of IL-21 in rheumatoid arthritis: current understanding and future perspectives. J Cell Physiol, 2018, 233(5): 3918-3928.
45. 王静, 赵庆杰, 卓小斌, 等. 类风湿性关节炎的治疗药物研究进展. 药学实践杂志, 2019, 37(6): 485-490.
46. Namba S, Nakano R, Kitanaka T, et al. ERK2 and JNK1 contribute to TNF-α-induced IL-8 expression in synovial fibroblasts. PLoS One, 2017, 12(8): e0182923.
47. 商玮. 姜黄素对类风湿关节炎患者 PBMC 破骨细胞生成的影响及可能机制的研究. 南京: 南京中医药大学, 2016.
48. Huang CC, Chiou CH, Liu SC, et al. Melatonin attenuates TNF-α and IL-1β expression in synovial fibroblasts and diminishes cartilage degradation: implications for the treatment of rheumatoid arthritis. J Pineal Res, 2019, 66(3): e12560.

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