Arthritis

Arthritis describes over 100 diseases involving joint inflammation (1, 2). JAK/STAT signaling, NF-κB signaling, Wnt signaling, p38 MAPK signaling, and PI3K/AKT signaling are a few of the pathways implicated in the pathogenesis of rheumatoid arthritis and osteoarthritis, the two most common types of arthritis.

The pathophysiology of arthritis varies depending on the type. Osteoarthritis, a degenerative whole-joint disorder and the most common form of arthritis, is characterized by gradual cartilage breakdown and subchondral bone remodeling (3). It is a complex disorder that happens due to the interaction between risk factors, abnormal joint mechanics, and joint wear and tear from injury or overuse (4).

Risk factors of osteoarthritis include aging, female sex, genetic predisposition, poor muscle strength, high-intensity exercise, a history of joint injury, hypertension, and obesity (5). People with osteoarthritis may show a range of symptoms, from mild to disabling, including loss of or limited joint function, pain, stiffness, and swelling (6). Genetic factors are estimated to  contribute between 35% and 65% to the pathogenesis of the diseases, with candidate genes including COL11A, COL9A1, Interleukin 1, 6, and 17, Asporin (ASP), Calmodulin (CALM1), and Matrilin-3 implicated in the disease process (7).

The second most common arthritis, rheumatoid arthritis, is a chronic, progressive, inflammatory autoimmune disease characterized by synovial inflammation and joint destruction, causing symptoms like joint swelling, pain, and damage, fever, osteoporosis, and muscle weakness (8).

Although rheumatoid arthritis primarily affects the joints, it may also affect other organs, including the heart, eyes, bones, blood vessels, lungs, kidneys, and skin (9). No one knows what exactly causes this disease, but susceptibility genes such as HLA-DRB1, TNFRSF14, PTPN22, CTLA4, and CTLA4 and environmental factors including exposure to tobacco smoke, air pollution, and lower vitamin D and antioxidants intake play significant roles in the development of rheumatoid arthritis. (10)

Signaling pathways involved in osteoarthritis

The pathogenesis of osteoarthritis is tied to signaling pathways, including the Wnt signaling pathway, p38 MAPK signaling pathway, and NF-κB pathway. Understanding the role of these signaling pathways in osteoarthritis may benefit drug development and lead to improved treatment of osteoarthritis.

The Wnt signaling pathway

Impaired activation of the Wnt (wingless-like) signaling pathway has been recognized to lead to pathological changes that occur with the development and progression of osteoarthritis (11).

Wnts are extracellularly secreted glycoproteins involved in processes such as cell fate determination, migration, proliferation, apoptosis, and tissue maintenance, repair and regeneration. Wnt signaling involves 19 Wnt genes and Wnt receptors and can act through either the canonical pathway that requires the transcription factor B-catenin or a non-canonical pathway that does not act through B-catenin(11).

The tight regulation of the Wnt signaling cascade is necessary for bone formation, growth and repair, and joint development (12, 13). Conversely, dysregulation of this pathway may lead to the development of joint and bone diseases like osteoarthritis and osteoporosis (13). For instance, excessive Wnt pathway activation by IL-1β is recognized as a predictor of osteoarthritis progression. It is involved in osteoarthritis progression as it promotes articular cartilage breakdown by increasing the expression of degrading enzymes aggrecanases and MMPs (matrix metalloproteinases) in chondrocytes and macrophages (14).

Researchers postulate the potential of targeting the Wnt pathway to help develop more effective therapies for osteoarthritis (15). Pre-approved drugs like Fluoxetine and Verapamil have been shown to inhibit abnormal Wnt activity and slow cartilage breakdown in vitro and rodent studies (12).

The NF-κB pathway

NF-κB pathway is also significantly involved in the pathological process of osteoarthritis (16). This pathway contributes to articular cartilage destruction by inducing the production of degradative enzymes, including ADAMTS4, ADAMTS5, and MMPs. NF-κB is also responsible for joint injury as it stimulates the production of PGE2 (prostaglandin E2), NOS (nitric oxide synthase), NO (nitric oxide), and COX2 (cyclooxygenase-2). These molecules are involved in events central to osteoarthritis progression, such as tissue inflammation, chondrocyte catabolism, and chondrocyte apoptosis (6).

The involvement of the NF-κB pathway in the initiation and progression of osteoarthritis makes it a recognized therapeutic target of osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are a few drugs that hinder this signaling pathway (17).

The p38 MAPK signaling pathway

The p38 MAPK signaling pathway is a well-recognized contributor to the pathogenesis of osteoarthritis. The p38 MAPK signaling pathway is a member of the MAPK signaling pathway family that is primarily activated by MAPKK3 and MAPKK6 (18).

The p38 MAPK signaling pathway has been found to contribute to and speed up osteoarthritis progression. It influences cartilage degeneration and chondrocyte damage by upregulating the expression of MMPs. This pathway is also recognized as an essential regulator of inflammatory mediators of osteoarthritis like pro-inflammatory cytokines TNF-α and IL-1β (18).

The pivotal role of the p38 MAPK signaling pathway in osteoarthritis makes it a target in the development of osteoarthritis treatment. In animal studies, selective p38-MAPK inhibitors have been found to block joint inflammation and destruction (19). Pyridinyl imidazoles, indoles, pyridines, and pyrimidines, are a few available p38 MAPK inhibitors but are associated with low drug selectivity and serious adverse effects (18).

Signaling pathways involved in Rheumatoid arthritis

The dysregulated activation of signaling pathways by pro-inflammatory cytokines such as IL-15, IL-17, and IL-18 leads to the production of inflammatory mediators of rheumatoid arthritis, such as proinflammatory cytokines, chemokines, adhesion molecules, and RANKL (20, 21, 22). According to researchers, primary signaling pathways involved in Rheumatoid arthritis include NF-κB, PI3K-AKT, and JAK/STAT.

The JAK/STAT pathway

The JAK/STAT signaling pathway consists of ligand-receptor complexes, JAKs, and STATs. When a ligand binds to a receptor involved in this pathway, JAKs (Janus family of kinases), become activated. Activation causes these intracellular non-receptor protein tyrosine kinases, to phosphorylate each other and tyrosines on the intracellular tails of the receptor, leading to the activation of STAT (signal transducer and activator of transcription) proteins. These STATs then bind to DNA and regulate gene expression.

JAK/STAT signaling is vital to immune function and cellular responses, such as cell proliferation, differentiation, migration, apoptosis, and survival (23, 24). Ideally, this pathway is tightly regulated.  But when dysregulated, this pathway may promote inflammation, abnormal development of blood-forming stem cells, and an uncontrolled immune response and is linked with the development and progression of chronic inflammatory diseases like rheumatoid arthritis (25, 9).

Abnormal activation of JAK/STAT signaling, mostly by cytokines IL-6 and IFN-γ in rheumatoid arthritis, is thought to play a crucial role in the rheumatoid arthritis-associated events, including synovial inflammation, synovial proliferation, autoantibody production, and joint destruction (9, 10).

Due to the relevance of the JAK/STAT signaling pathway to rheumatoid arthritis, researchers have explored them as targets for treatment. For instance, tofacitinib, a JAK inhibitor that disrupts the JAK/STAT signaling pathway and mRNA transcription, is used alone or with other medications to treat rheumatoid arthritis (20). Other JAK/STAT inhibitors approved for rheumatoid arthritis include baricitinib and upadacitinib (26).

The NF-κB signaling pathway

The NF-κB (Nuclear Factor-κB) signaling pathway is another critical pathway in the onset and progression of rheumatoid arthritis. NF-κB is a family of transcription factors comprising NF-κB1, NF-κB2, RelA, RelB, and c-Rel. It regulates genes involved in immune and inflammatory responses. (27).

NF-κB is abnormally activated in rheumatoid arthritis prominently by pro-inflammatory cytokines TNF and IL-1 (28). In turn, it promotes the release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF, significant mediators of inflammation in rheumatoid arthritis, thereby creating a vicious loop favoring rheumatoid arthritis progression (29).

The NF-κB signaling pathway is involved in synovial inflammation, inflammatory bone loss, auto-antibody production, and other pathological processes characteristic of rheumatoid arthritis (21, 27). Therapeutic agents interfering with this pathway, such as tacrolimus and bortezomib, have been explored as a stand-alone or combination rheumatoid arthritis treatment (30, 31)

Despite being a promising target for drug development, efficacy, specificity, and safety concerns persist. For instance, because NF-κB is involved in vital biological processes, unselective inhibition may attract adverse effects such as immunodeficiencies and hepatotoxicity (32). Hence, the need for more research and a better understanding of the role of NF-κB in rheumatoid arthritis and other inflammatory and autoimmune diseases.

The PI3K/AKT  signaling pathway

The involvement of the PI3K (phosphatidylinositol 3‑kinase)/AKT (protein kinase B) signaling pathway in the pathogenesis and development of rheumatoid arthritis is well established (29).  PI3K is a lipid kinase whose primary role is phosphorylating target lipids to generate second messengers such as PIP3, which in turn activate AKT and other downstream molecules. AKT is the main downstream target of PI3K (33).

The  PI3K/AKT  signaling pathway regulates cellular processes, including cell growth, proliferation, survival, and metabolism (34). Abnormal activation of the PI3K/AKT  signaling pathway in rheumatoid arthritis is linked to the aberrant proliferation of synovial fibroblasts, synovial inflammation, cartilage and bone destruction, and inflammation aggravation. It influences these pathological changes by triggering the expression of genes, including inflammatory cytokines IL-1β, IL-6, IL-17, IL-21, IL-22, and TNF-α, VEGF, and HIF-1α (29).

References

1. Huang H, Dong X, Mao K, Pan W, Nie B, Jiang L. Identification of key candidate genes and pathways in rheumatoid arthritis and osteoarthritis by integrated bioinformatical analysis. Front Genet. 2023;14:1083615. Published 2023 Feb 13.
2. Senthelal S, Li J, Ardeshirzadeh S, et al. Arthritis. [Updated 2022 Jun 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
3. Zhang C, Lin Y, Yan CH, Zhang W. Adipokine Signaling Pathways in Osteoarthritis. Front Bioeng Biotechnol. 2022;10:865370. Published 2022 Apr 19.
4. Sen R, Hurley JA. Osteoarthritis. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan
5. Tong L, Yu H, Huang X, et al. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Res. 2022;10(1):60. Published 2022 Sep 20.
6. Yao Q, Wu X, Tao C, et al. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):56. Published 2023 Feb 3.
7. Fernández-Moreno M, Rego I, Carreira-Garcia V, Blanco FJ. Genetics in osteoarthritis. Curr Genomics. 2008;9(8):542-547. 
8. Liu S, Ma H, Zhang H, Deng C, Xin P. Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. Clin Immunol. 2021;230:108793.
9. Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis [published correction appears in Ther Adv Musculoskelet Dis. 2018 Oct 08;10(11):225]. Ther Adv Musculoskelet Dis. 2018;10(5-6):117-127.
10. Tanaka Y, Luo Y, O'Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18(3):133-145.
11. Wang Y, Fan X, Xing L, Tian F. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun Signal. 2019;17(1):97. Published 2019 Aug 16.
12. Ng LF, Kaur P, Bunnag N, et al. WNT Signaling in Disease. Cells. 2019;8(8):826. Published 2019 Aug 3.
13. Cheng J, Li M, Bai R. The Wnt signaling cascade in the pathogenesis of osteoarthritis and related promising treatment strategies. Front Physiol. 2022;13:954454. Published 2022 Sep 2.
14. He Y, Li Z, Alexander PG, et al. Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models. Biology (Basel). 2020;9(8):194. Published 2020 Jul 29.
15. Sassi N, Laadhar L, Allouche M, et al. WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology. J Recept Signal Transduct Res. 2014;34(2):73-80.
16. Choi MC, Jo J, Park J, Kang HK, Park Y. NF-κB Signaling Pathways in Osteoarthritic Cartilage Destruction. Cells. 2019;8(7):734. Published 2019 Jul 17.
17. Rigoglou S, Papavassiliou AG. The NF-κB signalling pathway in osteoarthritis. Int J Biochem Cell Biol. 2013;45(11):2580-2584.
18. Li Z, Dai A, Yang M, Chen S, Deng Z, Li L. p38 MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects. J Inflamm Res. 2022;15:723-734. Published 2022 Feb 3.
19. Rasheed Z, Akhtar N, Haqqi TM. Pomegranate extract inhibits the interleukin-1β-induced activation of MKK-3, p38α-MAPK and transcription factor RUNX-2 in human osteoarthritis chondrocytes. Arthritis Res Ther. 2010;12(5):R195.
20. Zhang C. Flare-up of cytokines in rheumatoid arthritis and their role in triggering depression: Shared common function and their possible applications in treatment (Review). Biomed Rep. 2021;14(1):16.
21. Zhu M, Ding Q, Lin Z, et al. New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect. Biomolecules. 2023;13(5):766. Published 2023 Apr 28.
22. IntechOpen https://www.intechopen.com/chapters/52723  (accessed July 31, 2023)
23. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. Published 2021 Nov 26.
24. Harrison DA. The Jak/STAT pathway. Cold Spring Harb Perspect Biol. 2012;4(3):a011205. Published 2012 Mar 1.
25. Recio C, Guerra B, Guerra-Rodríguez M, et al. Signal transducer and activator of transcription (STAT)-5: an opportunity for drug development in oncohematology. Oncogene. 2019;38(24):4657-4668.
26. Simon LS, Taylor PC, Choy EH, et al. The Jak/STAT pathway: A focus on pain in rheumatoid arthritis. Semin Arthritis Rheum. 2021;51(1):278-284.
27. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.
28. van Loo G, Beyaert R. Negative regulation of NF-κB and its involvement in rheumatoid arthritis. Arthritis Res Ther. 2011;13(3):221. Published 2011 May 31.
29. Ding Q, Hu W, Wang R, et al. Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal Transduct Target Ther. 2023;8(1):68. Published 2023 Feb 17.
30. Dutta S, Ahmad Y. The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2011;3(6):283-291.
31. Verbrugge SE, Scheper RJ, Lems WF, de Gruijl TD, Jansen G. Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther. 2015;17(1):17. Published 2015 Jan 28.
32. Bennett J, Capece D, Begalli F, et al. NF-κB in the crosshairs: Rethinking an old riddle. Int J Biochem Cell Biol. 2018;95:108-112.
33. Xu Z, Shang W, Zhao Z, Zhang B, Liu C, Cai H. Curcumin alleviates rheumatoid arthritis progression through the phosphatidylinositol 3-kinase/protein kinase B pathway: an in vitro and in vivo study. Bioengineered. 2022;13(5):12899-12911.
34. Pompura SL, Dominguez-Villar M. The PI3K/AKT signaling pathway in regulatory T-cell development, stability, and function [published online ahead of print, 2018 Jan 22]. J Leukoc Biol. 2018;10.1002/JLB.2MIR0817-349R.