No retraction, correction or concern found when last checked on Oct 17, 2026.

Signaling pathways in rheumatoid arthritis: implications for targeted therapy

Qian Ding, Wei Hu, Ran Wang and 7 more

Signal Transduction and Targeted Therapy · 2023 · Review

Abstract

Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

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Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur. J. Rheumatol. 2017;4:161-165.
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Shi J, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun. Rev. 2014;13:225-230.
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136.
Wu CY, Yang HY, Luo SF, Lai JH. From rheumatoid factor to anti-citrullinated protein antibodies and anti-carbamylated protein antibodies for diagnosis and prognosis prediction in patients with rheumatoid arthritis. Int J. Mol. Sci. 2021;22:686.
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Shim JH, Stavre Z, Gravallese EM. Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif. Tissue Int. 2018;102:533-546.
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Umetsu DT, Katzen D, Jabara HH, Geha RS. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J. Immunol. 1986;136:440-445.
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Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug · 2020
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153.
Mor A, Abramson SB, Pillinger MH. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin. Immunol. 2005;115:118-128.
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Interleukin-6 in Rheumatoid Arthritis · 2020
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Bolli R, Dawn B, Xuan YT. Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc. Med. 2003;13:72-79.
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167.
Simon LS, et al. The Jak/STAT pathway: a focus on pain in rheumatoid arthritis. Semin. Arthritis Rheum. 2021;51:278-284.
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Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 2018;10:117-127.
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169.
JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future · 2020
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170.
Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist. Updat. 2010;13:67-78.
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171.
Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J. Cell Sci. 2004;117:1281-1283.
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174.
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175.
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179.
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“Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway · 2018
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183.
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Leonard WJ, Lin JX. Cytokine receptor signaling pathways. J. Allergy Clin. Immunol. 2000;105:877-888.
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185.
Immunohistochemistry of Janus Kinase 1 (JAK1) Expression in Vitiligo · 2018
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186.
He X, et al. Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015-2018). Expert Opin. Ther. Pat. 2019;29:137-149.
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Monari C, et al. A microbial polysaccharide reduces the severity of rheumatoid arthritis by influencing Th17 differentiation and proinflammatory cytokines production. J. Immunol. 2009;183:191-200.
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188.
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JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation · 2019
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190.
Blaszczyk K, et al. STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1. Biochem. J. 2015;466:511-524.
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Gao W, et al. Association between rs7574865 polymorphism in STAT4 gene and rheumatoid arthritis: an updated meta-analysis. Eur. J. Intern. Med. 2020;71:101-103.
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192.
El-Lebedy D, et al. Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clin. Rheumatol. 2017;36:1981-1987.
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193.
Ju JH, et al. Modulation of STAT-3 in rheumatoid synovial T cells suppresses Th17 differentiation and increases the proportion of Treg cells. Arthritis Rheum. 2012;64:3543-3552.
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Finnegan A, et al. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J. Immunol. 2002;169:3345-3352.
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Wang F, Sengupta TK, Zhong Z, Ivashkiv LB. Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J. Exp. Med. 1995;182:1825-1831.
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196.
Lee SY, et al. IL-17-mediated Bcl-2 expression regulates survival of fibroblast-like synoviocytes in rheumatoid arthritis through STAT3 activation. Arthritis Res. Ther. 2013;15:R31.
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197.
Oike T, et al. Stat3 as a potential therapeutic target for rheumatoid arthritis. Sci. Rep. 2017;7:10965.
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Tripathi SK, et al. Genome-wide analysis of STAT3-mediated transcription during early human Th17 cell differentiation. Cell Rep. 2017;19:1888-1901.
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199.
Ralph JA, Morand EF. MAPK phosphatases as novel targets for rheumatoid arthritis. Expert Opin. Ther. Targets. 2008;12:795-808.
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200.
Sujitha S, Rasool M. MicroRNAs and bioactive compounds on TLR/MAPK signaling in rheumatoid arthritis. Clin. Chim. Acta. 2017;473:106-115.
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201.
Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 2011;75:50-83.
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202.
Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev. 2012;92:689-737.
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203.
Gaestel M. MAPK-activated protein kinases (MKs): novel insights and challenges. Front. Cell Dev. Biol. 2015;3:88.
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Whitaker RH, Cook JG. Stress relief techniques: p38 MAPK determines the balance of cell cycle and apoptosis pathways. Biomolecules. 2021;11:1444.
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207.
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208.
Terazawa S, et al. The attenuated secretion of hyaluronan by UVA-exposed human fibroblasts is associated with up- and downregulation of HYBID and HAS2 expression via activated and inactivated signaling of the p38/ATF2 and JAK2/STAT3 cascades. Int J. Mol. Sci. 2021;22:2057.
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Zhang, J. et al. Inhibition against p38/MEF2C pathway by Pamapimod protects osteoarthritis chondrocytes hypertrophy. Panminerva Med. (2020).
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210.
Lin YP, 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;46:3328-3335.
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211.
Samarpita S, Rasool M. Cyanidin attenuates IL-17A cytokine signaling mediated monocyte migration and differentiation into mature osteoclasts in rheumatoid arthritis. Cytokine. 2021;142:155502.
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212.
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213.
Unique properties of TCR-activated p38 are necessary for NFAT-dependent T-cell activation. · 2018
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214.
Pargellis C, Regan J. Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr. Opin. Investig. Drugs. 2003;4:566-571.
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215.
Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs · 2010
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216.
Sun K, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr. Cartil. 2020;28:400-409.
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217.
Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol. Biosyst. 2015;11:1946-1954.
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PTEN: Tumor Suppressor and Metabolic Regulator · 2018
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219.
Sathe A, Nawroth R. Targeting the PI3K/AKT/mTOR pathway in bladder cancer. Methods Mol. Biol. 2018;1655:335-350.
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220.
Tsai CH, et al. Osteopontin inhibition of miR-129-3p enhances IL-17 expression and monocyte migration in rheumatoid arthritis. Biochim. Biophys. Acta Gen. Subj. 2017;1861:15-22.
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221.
Shoda H, et al. Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis. Arthritis. Res. Ther. 2017;19:111.
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Kwok SK, et al. Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum. 2012;64:740-751.
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Mitra A, Raychaudhuri SK, Raychaudhuri SP. IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine. 2012;60:38-42.
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224.
Dinesh P, Rasool M. Berberine inhibits IL-21/IL-21R mediated inflammatory proliferation of fibroblast-like synoviocytes through the attenuation of PI3K/Akt signaling pathway and ameliorates IL-21 mediated osteoclastogenesis. Cytokine. 2018;106:54-66.
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225.
Xuan W, et al. Osteoclast differentiation gene expression profiling reveals chemokine CCL4 mediates RANKL-induced osteoclast migration and invasion via PI3K pathway. Cell Biochem. Funct. 2017;35:171-177.
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227.
Ba X, et al. WTD attenuating rheumatoid arthritis via suppressing angiogenesis and modulating the PI3K/AKT/mTOR/HIF-1α pathway. Front. Pharmacol. 2021;12:696802.
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228.
Li GQ, et al. PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol. Cell Biochem. 2013;372:221-231.
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229.
Feng FB, Qiu HY. Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed. Pharmacother. 2018;102:1209-1220.
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230.
A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway · 2019
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231.
Suto T, Karonitsch T. The immunobiology of mTOR in autoimmunity. J. Autoimmun. 2020;110:102373.
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232.
Iwata S, et al. Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy. Arthritis Rheumatol. 2015;67:63-73.
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Corneth OBJ, Klein Wolterink RGJ, Hendriks RW. BTK signaling in B cell differentiation and autoimmunity. Curr. Top. Microbiol. Immunol. 2016;393:67-105.
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Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway · 2021
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235.
Rip J, et al. Toll-like receptor signaling drives Btk-mediated autoimmune disease. Front. Immunol. 2019;10:95.
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Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy. Haematologica. 2020;105:1494-1506.
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Gabizon R, London N. A fast and clean BTK inhibitor. J. Med. Chem. 2020;63:5100-5101.
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243.
Zhang D, Gong H, Meng F. Recent advances in BTK inhibitors for the treatment of inflammatory and autoimmune diseases. Molecules. 2021;26:4907.
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Lie DC, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370-1375.
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245.
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247.
Sun J, et al. MicroRNA-26b inhibits cell proliferation and cytokine secretion in human RASF cells via the Wnt/GSK-3β/β-catenin pathway. Diagn. Pathol. 2015;10:72.
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Coy JF, et al. Pore membrane and/or filament interacting like protein 1 (POMFIL1) is predominantly expressed in the nervous system and encodes different protein isoforms. Gene. 2002;290:73-94.
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Maes T, Barceló A, Buesa C. Neuron navigator: a human gene family with homology to unc-53, a cell guidance gene from Caenorhabditis elegans. Genomics. 2002;80:21-30.
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Nakaya Y, Sukowati EW, Wu Y, Sheng G. RhoA and microtubule dynamics control cell-basement membrane interaction in EMT during gastrulation. Nat. Cell Biol. 2008;10:765-775.
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Wang KS, et al. Family-based association analysis of NAV2 gene with the risk and age at onset of Alzheimer’s disease. J. Neuroimmunol. 2017;310:60-65.
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McNeill EM, Roos KP, Moechars D, Clagett-Dame M. Nav2 is necessary for cranial nerve development and blood pressure regulation. Neural Dev. 2010;5:6.
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Abo ElAtta AS, Ali YBM, Bassyouni IH, Talaat RM. Upregulation of miR-221/222 expression in rheumatoid arthritis (RA) patients: correlation with disease activity. Clin. Exp. Med. 2019;19:47-53.
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