Signaling pathways in rheumatoid arthritis: implications for targeted therapy

  • Post category:Rheumatology
  • Reading time:11 mins read
Dholka_Concord_Biotech

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that affects multiple joints symmetrically and can also affect other organs. It has a prevalence of around 1% globally and affects women more than men. The cause of RA is not fully understood but is believed to be related to both genetic and environmental factors. RA can lead to joint destruction, deformity, and disability, impacting quality of life and work productivity. The diagnosis of RA is based on physical manifestations and symptoms, and there is currently no cure for the disease. Recent research has focused on developing molecules that inhibit the signaling pathways involved in RA pathogenesis. This review discusses the risk factors and pathogenesis of RA, the signaling pathways involved, drugs in clinical use, potential drugs in clinical or preclinical studies, and technologies for targeted therapy.

Risk factors and symptoms

The cause of rheumatoid arthritis (RA) is a combination of environmental and genetic factors. The HLA-DRB1 gene is strongly associated with RA, and specific alleles may be related to the susceptibility and outcome of the disease. Environmental factors such as smoking and diet can also affect the development of RA. RA affects not only the joints but also other organs such as the eyes, skin, lungs, liver, heart, and bones. The disease is characterized by inflammation, swelling, fever, pain, and stiffness in the affected joints, with symptoms more pronounced after long periods of inactivity. Untreated chronic inflammation can lead to complications such as renal amyloidosis, rheumatoid nodules, and interstitial lung disease, as well as an increased risk of cardiovascular disease.

The pathogenesis of RA

Rheumatoid arthritis (RA) is a condition characterized by autoimmune response and inflammation, primarily in the joints. Fibroblast-like synoviocytes (FLS) play a crucial role in the disease’s pathological course. Three stages of RA progression include a non-specific inflammatory stage, chronic inflammatory stage, and tissue damage stage mediated by cytokines like IL-1, IL-6, and TNF-α, respectively. The production of autoantibodies, particularly against citrullinated peptides (ACPAs), has been linked to severe symptoms like joint injury and increased mortality. Joint swelling in RA is caused by synovial inflammation due to immune activation, with a cellular composition of innate and adaptive immune cells. The cascade drives chronic inflammation in RA, and fibroblast-like synoviocytes in the synovium form an invasive phenotype that exacerbates joint injury.

 

FLS and immune cells in RA

The role of stromal cells, particularly fibroblasts (FLS), in rheumatoid arthritis (RA) has gained attention. FLS normally maintain synovium homeostasis but transform into destructive and aggressive tumor-like cells in the presence of RA inflammation, producing cytokines, chemokines, and matrix metalloproteinases. Cytokines and chemokines promote inflammation by activating endothelial cells, attracting immune cells, and promoting differentiation of T and B cells. Osteoclast generation is triggered by monocytes, macrophages, and fibroblasts. Cytokines bind to receptors to activate genes that exacerbate inflammation and tissue damage. Granulocyte- monocyte colony-stimulating factor, interleukin-6, and tumor necrosis factor are essential to the process.

Signaling pathways in thepathogenesis of RA

Multiple signal transduction pathways are involved in the disease progression of rheumatoid arthritis, the major signaling pathways are shown in Fig. 2, and the abnormal signals are often targets for drug discovery.

The JAK-STAT signaling pathway

The JAK-STAT (Janus-activated Kinase-Signal Transduction and Activator of Transcription) pathway is important for cytokine signaling and has been found to be abnormally activated in rheumatoid arthritis (RA). The pathway is involved in regulating inflammation and immune function and plays a crucial role in cell differentiation, proliferation, apoptosis, and immune function. JAK family has four members, and studies have shown that JAK plays an important role in RA. STAT is a family of cytoplasmic proteins with both transcriptional activation and signal transduction functions. The occurrence and progression of RA have been highly correlated to the abnormal activation of the JAK-STAT pathway. Synovitis is the pathological basis of RA, and many inflammatory reactions have been observed in RA synoviums. The inhibition of JAK2 and STAT1 can treat RA by inhibiting the generation of cytokines and the activation of T and B-lymphocytes.

 

The MAPK signaling pathway and RA

The MAPK signaling pathway is important in regulating various cellular activities and is closely linked to the pathological process of rheumatoid arthritis (RA). P38 MAPK is the most important member of the MAPK family linked to the inflammatory response in RA and is activated in endogenous immune cells such as neutrophils and monocytes. P38 MAPK can activate transcription factors and induce a large increase in inflammatory chemokines, resulting in synovial thickening. P38 MAPK can also inhibit cell apoptosis and plays a role in T cell differentiation. Therefore, P38 is considered a candidate target for treating RA.

The PI3K-AKT signaling pathway in RA

The PI3K-AKT pathway is an intracellular pathway that regulates proliferation, metabolism, angiogenesis, and cell survival in response to extracellular signals. It has been proven that the abnormal activation of this pathway is correlated with the occurrence and development of rheumatoid arthritis (RA). The pathway stimulates the expression of inflammatory molecules and cytokines that contribute to the pathogenesis of RA. Additionally, the pathway promotes angiogenesis, which isolates bones from nutrients and releases inflammatory mediators, further aggravating the condition of RA. The mammalian target of rapamycin (mTOR) in the PI3K/AKT/mTOR pathway inhibits autophagy, promotes abnormal proliferation of synovial cells, and is critical for the survival and differentiation of osteoclasts, aggravating RA. mTOR could be a potential target for the treatment of RA and other autoimmune diseases.

SYK signaling pathway in RA

SYK and BTK are two key molecules involved in B-cell receptor signaling, and their dysregulation has been linked to the pathogenesis of rheumatoid arthritis (RA). In RA patients, there is an increase in the levels of phosphorylated SYK and BTK in peripheral B cells, and this is correlated with the production of autoantibodies. BTK is also involved in regulating B-cell survival, proliferation, and cytokine production, and it mediates bone resorption by regulating osteoclast proliferation and differentiation. Therefore, BTK is considered an attractive target for treating autoimmune diseases like RA.

Wnt signaling pathway in RA

The Wnt signaling pathway plays a crucial role in RA pathogenesis by regulating synovial inflammation and bone metabolism. NAV2, a neuro-guiding protein, is involved in various cellular processes and has been shown to promote inflammatory responses in fibrocyte- like synoviocytes via the Wnt/β-catenin and SSH1L/Cofilin-1 signaling pathways in RA. Inhibition of NAV2 expression has been found to prevent RA progression and reverse inflammation-related phenotypes, making it a promising intervention target for RA treatment.

Epigenetics regulation in RA signaling pathway

Epigenetics refers to heritable changes in gene expression without altering DNA sequence, which can determine which genes are turned on or off. This process involves histone modification, DNA methylation, and non-coding RNA mechanisms. These modifications define specific gene expression patterns, and genetic and environmental factors interact to determine gene expression. Histone modifications, such as acetylation, methylation, and phosphorylation, can inhibit or activate gene expression, and histone modification enzymes are proposed as drug targets for RA. DNA methylation, which occurs at CpG islands in the promoter region, can lead to gene silencing and is a potential therapeutic target. Abnormal cytosine methylation occurs in the promoter regions of IL-6 and IL-10 in RA patients, affecting transcription. Studies have shown that DNA methylation levels in T cells and monocytes in RA patients are lower than those in healthy subjects.

Targeted therapy for RA

This text provides information about drugs used to treat rheumatoid arthritis (RA). Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, which leads to the inhibition of prostaglandins synthesis, resulting in antipyretic and analgesic effects. However, excessive or prolonged use of NSAIDs can lead to several side effects, such as leukopenia, thrombocytopenia, digestive tract lesions, liver damage, and kidney damage. Methotrexate (MTX) is the most commonly used conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) used to treat RA, and leflunomide and sulfasalazine are other drugs used in this class. Biological DMARDs (bDMARDs), such as Actemra, Kevzara, Enbrel, Humira, Remicade, Simponi, Orencia, and Rituxan, and targeted synthetic DMARDs (tsDMARDs), such as tofacitinib, baricitinib, and upadacitinib, are other drugs used to treat RA. The text provides information about the mechanism of action and side effects of each of these drugs. Researchers are developing drugs for rheumatoid arthritis (RA) that target various proteins involved in the inflammatory process. BTK inhibitors, such as Fenebrutinib, have shown promising results in clinical trials. JAK inhibitors like Ruxolitinib and VX-509 are also being studied. P38 kinase inhibitors like VX-702 have shown some efficacy but no sustained inhibition of inflammation. In pre-clinical studies, drugs targeting PI3K, mTOR, Notch signaling, and DNA methylation and HDAC enzymes have shown potential. Many of these drugs are being developed to reduce inflammation and joint damage associated with RA.

Conclusion

Rheumatoid arthritis is an autoimmune disease that causes joint damage and deformities, and current treatments only delay disease progression and have side effects. Pro-inflammatory cytokines play a role in RA pathogenesis, and targeting signal transduction pathways such as MAPK, WNT, PI3K/AKT, SYK, and JAK/STAT may be effective in treating RA. New technologies such as protein degradation using PROTAC technology, nanoparticles for drug delivery, and CRISPR-Cas9 genome editing may also hold promise for RA treatment. Personalized therapy is the goal for RA treatment in the future.

 

References:

1. Paget, S. A., Lockshin, M. D. & Loebl, S. The hospital for special surgery rheumatoid arthritis handbook: everything you need to know. (Wiley, 2002).
2. Senthelal, S., Li, J., Ardeshirzadeh, S. & Thomas, M. A. in StatPearls (StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC., 2022).
3. Landré-Beauvais, A. J. The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800. Jt. Bone Spine 68, 130–143 (2001).
4. Garrod, A.B. The nature and treatment of gout and rheumatic gout. Br. Foreign Med. Chir. Rev. 25, 419–435 (1860).
5. Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).
6. Radu, A. F. & Bungau, S. G. Management of rheumatoid arthritis: an overview. Cells 10, 2857 (2021).
7. Otón, T. & Carmona, L. The epidemiology of established rheumatoid arthritis. Best. Pract. Res. Clin. Rheumatol. 33, 101477 (2019).
8. Wasserman, A. Rheumatoid arthritis: common questions about diagnosis and management. Am. Fam. Physician 97, 455–462 (2018).
9. Almutairi, K. et al. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol. Int. 41, 863–877 (2021).
10. Safiri, S. et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017. Ann. Rheum. Dis. 78, 1463–1471 (2019)..
11. Azer, S. A., AlSwaidan, N. M., Alshwairikh, L. A. & AlShammari, J. M. Accuracy and readability of cardiovascular entries on Wikipedia: are they reliable learning resources for medical students? BMJ Open. 5, e008187 (2015).
12. Alamanos, Y., Voulgari, P. V. & Drosos, A. A. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 36, 182–188 (2006).
13. Goodson, N. & Symmons, D. Rheumatoid arthritis in women: still associated with an increased mortality. Ann. Rheum. Dis. 61, 955–956 (2002).
14. Kolarz, K., Targoriska-Stepniak, B. & Majdan, M. [Early reumatoid arthritis]. Wiad. Lek. 71, 1061–1065 (2018).
15. Kay, J. & Upchurch, K. S. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology 51, vi5–vi9 (2012).