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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Abstract Full text Figures/Tables Video References Cited by

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.	張彥景, 張建新. MAPK 信號轉導通路與類風濕關節炎的研究進展. 河北醫藥, 2016, 38(17): 2677-2681.
2.	周春燕, 藥立波. 生物化學與分子生物學. 北京: 人民衛生出版社, 1978: 327-345.
3.	Rubinfeld H, Seger R. The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol, 2005, 31(2): 151-174.
4.	陳曉俊, 王健英, 金素安, 等. 中藥影響類風濕性關節炎信號通路的研究進展. 中華中醫藥學刊, 2016, 34(7): 1735-1739.
5.	孫明慧, 吳虹, 卜妍紅, 等. 介導缺氧誘導因子-1α表達的相關信號通路在類風濕性關節炎中的研究進展. 中國藥理學通報, 2019, 35(9): 1197-1202.
6.	韓海燕, 沈敬華. 類風濕關節炎發病機制的研究進展. 世界最新醫學信息文摘, 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.	牛紅青. 基于 JAK2/STAT3 和 p38MAPK 信號通路探討環磷酰胺聯合甲氨蝶呤抑制類風濕關節炎成纖維樣滑膜細胞 RANKL 表達的研究. 太原: 山西醫科大學, 2018.
16.	王慧蓮, 孟慶良, 李松偉, 等. 漢黃芩素通過激活活性氧簇介導的 p38MAPK 信號通路誘導類風濕關節炎成纖維樣滑膜細胞凋亡. 中國骨質疏松雜志, 2017, 23(7): 890-895.
17.	羅素. 大黃素對 TNF-α誘導的成纖維樣滑膜細胞株 MH7A 細胞 ERK1/2 和 p38MAPK 的影響. 重慶: 重慶醫科大學, 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.	劉春芳, 何蓮花, 王靖霞, 等. 風濕祛痛膠囊對類風濕關節炎滑膜 Akt 和 MAPK 信號通路的影響. 中國實驗方劑學雜志, 2019, 25(13): 35-40.
20.	王霞, 蔣禮, 何燕玲, 等. 黑骨藤中咖啡酰基奎寧酸類化合物體外抗類風濕性關節炎機制研究. 中國藥理學通報, 2018, 34(10): 1362-1367.
21.	楊敏, 洪夢琴, 范星宇. RANKL-RANK-OPG 信號通路對類風濕關節炎骨破壞作用的研究進展. 醫學與哲學, 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.	陳紅梅, 王友蓮. 破骨細胞在類風濕關節炎致骨破壞病理變化中的作用及其調控. 中國骨質疏松雜志, 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, 韋婷, 童東, 等. 基于 MAPK 通路研究五味甘露藥浴散加減方治療類風濕關節炎的藥效機制. 中國中藥雜志, 2017, 42(7): 1245-1250.
34.	羅素, 榮曉鳳, 彭菲菲. 大黃素對 TNF-α誘導的成纖維樣滑膜細胞株 MH7A 細胞 ERK1/2 和 p38MAPK 的影響. 免疫學雜志, 2017, 33(2): 113-117.
35.	汪榮盛, 劉佳, 童萍, 等. 雷藤舒對 TNF-α誘導的人類風濕關節炎滑膜成纖維細胞促凋亡、抗炎及對 Ras-MAPKs 信號通路的調節作用. 上海中醫藥大學學報, 2016, 30(3): 82-87.
36.	唐敏. 馬錢子堿對 TNF-α誘導人類風濕關節炎成纖維樣滑膜細胞的增殖影響和 MAPK 通路中 JNK 調控的研究. 瀘州: 瀘州醫學院, 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. 類風濕關節炎免疫治療藥物的作用機制和應用進展. 中國處方藥, 2020, 18(4): 25-26.
39.	莫選榮, 謝江文, 呂國菊, 等. TAK1 基因沉默對 TNF-α誘導的滑膜細胞 IL-6、IL-8 表達的影響. 中國應用生理學雜志, 2017, 33(5): 471-475.
40.	唐莼, 李昀, 林小軍, 等. 泌乳素促進類風濕關節炎患者外周血單個核細胞分泌白細胞介素-6. 中國病理生理雜志, 2016, 32(11): 2062-2066.
41.	董佳莉. IL-6 調控類風濕關節炎患者外周血淋巴細胞 P-糖蛋白信號轉導通路的研究. 太原: 山西醫科大學, 2016.
42.	歐陽尋麗, 李寒, 孫曉彤, 等. 白細胞介素-34 對類風濕關節炎成纖維樣滑膜細胞 CCL28 表達的影響. 中國免疫學雜志, 2018, 34(2): 239-242.
43.	衛丹丹. 1, 25(OH)₂D₃ 對類風濕關節炎成纖維滑膜細胞 IL-22 介導的 RANKL 蛋白表達的影響. 太原: 山西醫科大學, 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.	王靜, 趙慶杰, 卓小斌, 等. 類風濕性關節炎的治療藥物研究進展. 藥學實踐雜志, 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.	商瑋. 姜黃素對類風濕關節炎患者 PBMC 破骨細胞生成的影響及可能機制的研究. 南京: 南京中醫藥大學, 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. 張彥景, 張建新. MAPK 信號轉導通路與類風濕關節炎的研究進展. 河北醫藥, 2016, 38(17): 2677-2681.
2. 周春燕, 藥立波. 生物化學與分子生物學. 北京: 人民衛生出版社, 1978: 327-345.
3. Rubinfeld H, Seger R. The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol, 2005, 31(2): 151-174.
4. 陳曉俊, 王健英, 金素安, 等. 中藥影響類風濕性關節炎信號通路的研究進展. 中華中醫藥學刊, 2016, 34(7): 1735-1739.
5. 孫明慧, 吳虹, 卜妍紅, 等. 介導缺氧誘導因子-1α表達的相關信號通路在類風濕性關節炎中的研究進展. 中國藥理學通報, 2019, 35(9): 1197-1202.
6. 韓海燕, 沈敬華. 類風濕關節炎發病機制的研究進展. 世界最新醫學信息文摘, 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. 牛紅青. 基于 JAK2/STAT3 和 p38MAPK 信號通路探討環磷酰胺聯合甲氨蝶呤抑制類風濕關節炎成纖維樣滑膜細胞 RANKL 表達的研究. 太原: 山西醫科大學, 2018.
16. 王慧蓮, 孟慶良, 李松偉, 等. 漢黃芩素通過激活活性氧簇介導的 p38MAPK 信號通路誘導類風濕關節炎成纖維樣滑膜細胞凋亡. 中國骨質疏松雜志, 2017, 23(7): 890-895.
17. 羅素. 大黃素對 TNF-α誘導的成纖維樣滑膜細胞株 MH7A 細胞 ERK1/2 和 p38MAPK 的影響. 重慶: 重慶醫科大學, 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. 劉春芳, 何蓮花, 王靖霞, 等. 風濕祛痛膠囊對類風濕關節炎滑膜 Akt 和 MAPK 信號通路的影響. 中國實驗方劑學雜志, 2019, 25(13): 35-40.
20. 王霞, 蔣禮, 何燕玲, 等. 黑骨藤中咖啡酰基奎寧酸類化合物體外抗類風濕性關節炎機制研究. 中國藥理學通報, 2018, 34(10): 1362-1367.
21. 楊敏, 洪夢琴, 范星宇. RANKL-RANK-OPG 信號通路對類風濕關節炎骨破壞作用的研究進展. 醫學與哲學, 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. 陳紅梅, 王友蓮. 破骨細胞在類風濕關節炎致骨破壞病理變化中的作用及其調控. 中國骨質疏松雜志, 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, 韋婷, 童東, 等. 基于 MAPK 通路研究五味甘露藥浴散加減方治療類風濕關節炎的藥效機制. 中國中藥雜志, 2017, 42(7): 1245-1250.
34. 羅素, 榮曉鳳, 彭菲菲. 大黃素對 TNF-α誘導的成纖維樣滑膜細胞株 MH7A 細胞 ERK1/2 和 p38MAPK 的影響. 免疫學雜志, 2017, 33(2): 113-117.
35. 汪榮盛, 劉佳, 童萍, 等. 雷藤舒對 TNF-α誘導的人類風濕關節炎滑膜成纖維細胞促凋亡、抗炎及對 Ras-MAPKs 信號通路的調節作用. 上海中醫藥大學學報, 2016, 30(3): 82-87.
36. 唐敏. 馬錢子堿對 TNF-α誘導人類風濕關節炎成纖維樣滑膜細胞的增殖影響和 MAPK 通路中 JNK 調控的研究. 瀘州: 瀘州醫學院, 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. 類風濕關節炎免疫治療藥物的作用機制和應用進展. 中國處方藥, 2020, 18(4): 25-26.
39. 莫選榮, 謝江文, 呂國菊, 等. TAK1 基因沉默對 TNF-α誘導的滑膜細胞 IL-6、IL-8 表達的影響. 中國應用生理學雜志, 2017, 33(5): 471-475.
40. 唐莼, 李昀, 林小軍, 等. 泌乳素促進類風濕關節炎患者外周血單個核細胞分泌白細胞介素-6. 中國病理生理雜志, 2016, 32(11): 2062-2066.
41. 董佳莉. IL-6 調控類風濕關節炎患者外周血淋巴細胞 P-糖蛋白信號轉導通路的研究. 太原: 山西醫科大學, 2016.
42. 歐陽尋麗, 李寒, 孫曉彤, 等. 白細胞介素-34 對類風濕關節炎成纖維樣滑膜細胞 CCL28 表達的影響. 中國免疫學雜志, 2018, 34(2): 239-242.
43. 衛丹丹. 1, 25(OH)₂D₃ 對類風濕關節炎成纖維滑膜細胞 IL-22 介導的 RANKL 蛋白表達的影響. 太原: 山西醫科大學, 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. 王靜, 趙慶杰, 卓小斌, 等. 類風濕性關節炎的治療藥物研究進展. 藥學實踐雜志, 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. 商瑋. 姜黃素對類風濕關節炎患者 PBMC 破骨細胞生成的影響及可能機制的研究. 南京: 南京中醫藥大學, 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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