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Popular Reports / rheumatology

This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of rheumatoid arthritis? ​

Abstract ​

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent joint inflammation, leading to pain, swelling, and irreversible joint damage. The multifactorial etiology of RA encompasses genetic predisposition, environmental triggers, and immune system dysregulation, contributing to its significant public health burden. Genetic factors, particularly the HLA-DRB1 gene, have been identified as key contributors to disease susceptibility, while environmental influences such as smoking and infectious agents further heighten risk. The immune system plays a pivotal role in RA pathogenesis, with T cells and B cells driving the autoimmune response through the production of pro-inflammatory cytokines and autoantibodies. Pro-inflammatory cytokines like IL-1, IL-6, and TNF-alpha are crucial mediators of inflammation, sustaining synovial inflammation and joint destruction. Mechanisms of joint damage include osteoclast activation leading to bone resorption and cartilage degradation processes mediated by metalloproteinases. Understanding these complex mechanisms is essential for identifying novel therapeutic targets and optimizing treatment strategies. This review synthesizes current knowledge on the mechanisms of RA, aiming to inform future research directions and enhance patient management.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Genetic Factors in Rheumatoid Arthritis
    • 2.1 Genetic Predisposition and Risk Alleles
    • 2.2 Role of the HLA-DRB1 Gene
  • 3 Environmental Triggers
    • 3.1 Infectious Agents
    • 3.2 Smoking and Other Lifestyle Factors
  • 4 Immune System Dysregulation
    • 4.1 Role of T Cells in RA Pathogenesis
    • 4.2 Contribution of B Cells and Antibody Production
  • 5 Cytokine Signaling and Inflammation
    • 5.1 Pro-inflammatory Cytokines: IL-1, IL-6, and TNF-alpha
    • 5.2 Mechanisms of Synovial Inflammation
  • 6 Joint Destruction Mechanisms
    • 6.1 Osteoclast Activation and Bone Resorption
    • 6.2 Cartilage Degradation Processes
  • 7 Summary

1 Introduction ​

Rheumatoid arthritis (RA) is a complex and chronic autoimmune disorder characterized by persistent inflammation of the synovial joints, leading to pain, swelling, and ultimately, irreversible joint damage. The multifactorial etiology of RA includes genetic predisposition, environmental triggers, and immune system dysregulation, making it a significant public health concern globally, with an estimated prevalence of 0.1% to 2% in various populations [1]. The complexity of RA is underscored by its association with increased morbidity and mortality, particularly due to cardiovascular complications [2]. Despite advancements in understanding the disease, the precise mechanisms driving RA pathogenesis remain incompletely elucidated, highlighting the necessity for ongoing research to uncover the underlying biological processes.

The significance of studying RA mechanisms lies in their implications for developing targeted therapies and improving patient outcomes. Current treatments, including disease-modifying antirheumatic drugs (DMARDs) and biologics, aim to mitigate symptoms and prevent disease progression. However, these therapies often come with substantial side effects and may not be effective for all patients [1][1]. Understanding the intricate interplay between genetic factors, environmental influences, and immune responses is essential for identifying novel therapeutic targets and optimizing treatment strategies [3][4].

Recent studies have elucidated several key aspects of RA pathogenesis. Genetic factors, particularly the HLA-DRB1 gene, have been identified as critical contributors to disease susceptibility [5]. Environmental triggers, such as smoking and infectious agents, further exacerbate the risk of developing RA [6]. The role of the immune system, especially the activation of T cells and the production of autoantibodies by B cells, is pivotal in the disease's progression [7]. Additionally, pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, play crucial roles in sustaining synovial inflammation and joint destruction [1][8].

This review will systematically explore the mechanisms underlying RA, organized into several key sections. The first section will address genetic factors in RA, focusing on genetic predisposition and the specific role of the HLA-DRB1 gene. The subsequent section will examine environmental triggers, including infectious agents and lifestyle factors such as smoking. Following this, we will delve into the dysregulation of the immune system, with a focus on the contributions of T cells and B cells to RA pathogenesis. The next section will cover cytokine signaling and inflammation, detailing the roles of pro-inflammatory cytokines and the mechanisms of synovial inflammation. Subsequently, we will discuss the mechanisms of joint destruction, including osteoclast activation and cartilage degradation processes. Finally, the review will summarize the findings and highlight areas for future research.

By synthesizing current knowledge on the mechanisms of RA, this review aims to provide a comprehensive understanding of the disease's pathophysiology and inform future therapeutic strategies. Ultimately, elucidating these mechanisms is crucial for advancing the management of RA and improving the quality of life for affected individuals.

2 Genetic Factors in Rheumatoid Arthritis ​

2.1 Genetic Predisposition and Risk Alleles ​

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by chronic inflammation and progressive joint destruction, with a significant contribution from genetic factors. The genetic predisposition for RA is largely attributed to specific alleles within the major histocompatibility complex (MHC), particularly the HLA-DRB1 gene, which is associated with the "shared epitope" hypothesis. This hypothesis posits that certain alleles encoding antigen-presenting molecules can predispose individuals to RA by influencing the immune response to citrullinated proteins, which are key autoantigens in the disease pathogenesis[5].

Research has identified over 100 susceptibility loci associated with RA, with a substantial proportion of these linked to the HLA region. The strongest genetic association has been noted with the HLA-DRB1 alleles, which encode for a unique sequence in the peptide-binding groove that is crucial for antigen presentation. This genetic risk is not uniform; it appears to differ significantly between anti-cyclic citrullinated peptide (ACPA)-positive and ACPA-negative RA[9][10].

In addition to HLA alleles, other non-MHC genetic variants have been implicated in RA pathogenesis. For instance, polymorphisms in genes such as PTPN22, TRAF1-C5, PADI4, and STAT4 have been associated with increased susceptibility to RA[11]. These genetic factors contribute to the complexity of the disease by influencing various immunological pathways and responses. However, genetic factors alone do not fully account for the disease; environmental factors also play a crucial role in the onset and progression of RA[12].

The interplay between genetic predisposition and environmental triggers, such as smoking and infections, has been shown to exacerbate the risk of developing RA. Notably, smoking has been linked to the promotion of ACPA-positive RA, suggesting that gene-environment interactions are critical in understanding individual susceptibility to the disease[13].

Genome-wide association studies (GWAS) have further elucidated the genetic landscape of RA, identifying additional risk alleles and contributing to the development of genetic risk profiles for affected individuals. Despite these advancements, a significant proportion of familial RA cases remain unexplained, indicating that there are likely more genetic factors yet to be identified[14].

Overall, the genetic underpinnings of RA involve a complex network of risk alleles that interact with environmental factors, leading to dysregulation of the immune system and the subsequent development of autoimmune responses. Understanding these mechanisms is essential for identifying individuals at high risk and developing targeted therapeutic strategies to prevent or mitigate the disease's progression.

2.2 Role of the HLA-DRB1 Gene ​

Rheumatoid arthritis (RA) is a multifactorial autoimmune disorder characterized by chronic inflammation, joint destruction, and varying clinical manifestations. A significant body of research has established the pivotal role of genetic factors, particularly the human leukocyte antigen (HLA) genes, in the pathogenesis of RA. Among these, the HLA-DRB1 gene is particularly noteworthy due to its strong association with disease susceptibility.

The genetic predisposition to RA is largely influenced by specific alleles of the HLA-DRB1 gene. Studies have identified that HLA-DRB1 molecules containing certain amino acid sequences, particularly those with the motifs QKRAA, QRRAA, or RRRAA at positions 70-74 in the third hypervariable region of the DRB1 chain, are associated with an increased risk of developing RA. These specific sequences are often referred to as the "shared epitope" and are found in several high-risk alleles such as HLA-DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, and *1402 [15]. Conversely, HLA-DRB1 alleles containing the amino acid sequence "DERAA" at the same positions are linked to a protective effect against RA [15].

The HLA-DRB1 gene not only contributes to genetic susceptibility but also plays a role in the immunological mechanisms underlying RA. It is involved in the presentation of antigens to T cells, which is crucial for initiating the immune response. Variations in the HLA-DRB1 gene can affect the binding affinity of these molecules to specific peptides, thereby influencing T cell activation and the subsequent inflammatory response [16]. This interaction is critical in the context of RA, where the immune system erroneously targets synovial tissue, leading to joint inflammation and damage.

Moreover, research indicates that the HLA-DRB1 gene's influence extends beyond inherited factors; non-inherited maternal antigens (NIMA) also contribute to RA susceptibility. For instance, the presence of "DERAA"-containing HLA-DRB1 alleles from the mother has been shown to exert a protective effect on offspring [15].

In addition to HLA-DRB1, other genetic loci and non-HLA genes have been implicated in RA. Although HLA genes account for a substantial proportion of genetic risk, it has been estimated that only about 30% of the genetic contribution to RA can be attributed to HLA genes alone. Non-HLA genes such as PTPN22, TRAF1, and STAT4 also confer risk and are believed to interact with environmental factors, further complicating the genetic landscape of RA [17].

The intricate interplay of genetic susceptibility, particularly involving the HLA-DRB1 gene, and environmental factors is essential in understanding the pathogenesis of RA. Ongoing research aims to elucidate these mechanisms further, with the goal of developing targeted therapies and improving diagnostic and prognostic capabilities in RA management [18].

3 Environmental Triggers ​

3.1 Infectious Agents ​

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation, primarily affecting the joints. While the precise etiology of RA remains unclear, numerous studies have highlighted the significant role of environmental triggers, particularly infectious agents, in the disease's pathogenesis.

Infectious agents are considered major environmental factors that may provoke inflammatory arthritides in genetically susceptible individuals. Two primary pathogenetic pathways have been proposed regarding how infections can initiate and perpetuate chronic arthritides: persistent infection and the induction of immunopathology. Evidence suggests that various microorganisms, including retroviruses and enteropathogenic bacteria, may act as potential etiological factors in RA, although direct proof linking specific infectious agents to the disease is still lacking (Krause et al., 1996) [19].

The interaction between infectious agents and the immune system is critical in the development of RA. It has been suggested that the immune response may be inadequately regulated, leading to an inappropriate reaction to these environmental challenges. In particular, the presence of infectious agents may provoke a hyperactive immune response, resulting in the production of autoantibodies and subsequent synovial hyperplasia and bone destruction (Calabresi et al., 2018) [20].

A growing body of literature indicates that infectious agents could potentially trigger RA through various mechanisms. For instance, certain microorganisms may share antigenic motifs with self-antigens, which can confuse the immune system and lead to an autoimmune response. Additionally, it is posited that infections might not trigger RA in all individuals but could do so in genetically predisposed individuals or in combination with other factors such as psychological stress and chronic joint tissue microtrauma (Arleevskaya et al., 2016) [21].

Moreover, environmental factors such as smoking and dietary influences are also thought to interact with infectious agents, exacerbating the risk of developing RA. The dysbiosis of gut microbiota has been implicated as a contributing factor, with significant differences in gut microbiota composition observed in RA patients compared to healthy controls (Attur et al., 2022) [22].

In summary, while genetic predisposition plays a crucial role in RA, environmental factors, particularly infectious agents, are vital triggers that may initiate the disease process in susceptible individuals. Understanding these interactions can help elucidate the complex mechanisms underlying RA and may pave the way for new therapeutic strategies targeting these pathways.

3.2 Smoking and Other Lifestyle Factors ​

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation and damage, with its etiology considered multifactorial, involving interactions between genetic and environmental factors. Among the environmental triggers, cigarette smoking is recognized as a significant risk factor, accounting for approximately one in six new cases of RA. The mechanisms through which smoking contributes to RA development are complex and multifaceted.

Firstly, smoking induces oxidative stress and inflammation, which are critical processes in the pathophysiology of RA. The exposure to cigarette smoke can lead to the formation of autoantibodies, such as anti-citrullinated protein antibodies (ACPAs) and rheumatoid factors (RF), which are commonly associated with unfavorable disease outcomes in RA patients [23][24]. The presence of these autoantibodies can precede the clinical onset of RA by several years, suggesting that smoking may trigger immunological changes long before the manifestation of the disease [25].

Recent studies have demonstrated that the relationship between smoking and RA is not solely a direct effect; rather, it involves complex gene-environment interactions. For instance, certain genetic predispositions, such as the presence of shared epitope alleles (SE), significantly amplify the risk of developing seropositive RA in smokers [26]. This gene-environment interaction indicates that individuals with specific genetic backgrounds may be more susceptible to the harmful effects of smoking, leading to increased autoantibody production and subsequent joint inflammation [27].

Additionally, the timing and intensity of smoking exposure are crucial factors in determining the extent of its impact on RA development. Studies using murine models have shown that the timing of cigarette smoke exposure can influence disease outcomes, with dose-dependent increases in disease manifestations correlating with the intensity of smoking [28]. This suggests that both the duration and the amount of smoking are important determinants in the pathogenesis of RA.

Moreover, smoking is linked to poorer responses to RA treatments, particularly anti-tumor necrosis factor (anti-TNF) therapies. Heavy smokers tend to have a diminished response to these treatments, potentially due to the immunological changes induced by smoking that interfere with therapeutic efficacy [23].

Beyond smoking, other lifestyle factors such as obesity, nutrition, and occupational exposures also contribute to RA risk. These factors can interact with the immune system, influencing inflammation and autoantibody production, although the precise mechanisms remain less well understood [29].

In summary, smoking is a well-established environmental risk factor for RA, acting through mechanisms that include oxidative stress, inflammation, autoantibody formation, and interactions with genetic predispositions. Understanding these mechanisms is crucial for developing targeted prevention and treatment strategies for individuals at risk of RA.

4 Immune System Dysregulation ​

4.1 Role of T Cells in RA Pathogenesis ​

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction, with a significant role played by T cells in its pathogenesis. The mechanisms underlying RA involve a complex interplay of immune system dysregulation, particularly through T cell activation and the interactions between various immune cell types.

T cells are pivotal in the pathogenesis of RA, likely participating continuously from disease initiation to its chronic phase. They interact with macrophages and mesenchymal cells through autocrine, paracrine, and cell-contact pathways, which contribute to the inflammatory milieu characteristic of RA [30]. The dysregulation of T cells, including the emergence of effector T cells that invade tissues and the functional impairment of regulatory T cells (Tregs), is crucial in driving disease progression [31].

Recent studies have identified distinct metabolic patterns in T cells from RA patients. These T cells exhibit a dampened glycolytic flux and poor ATP production, alongside a shift in glucose metabolism towards the pentose phosphate pathway, resulting in increased NADPH levels and decreased reactive oxygen species (ROS) [32]. This metabolic dysfunction is linked to mitochondrial and lysosomal abnormalities, which contribute to the aggressive phenotype of T cells in RA. Specifically, defective mitochondrial DNA repair and inefficient lysosomal function have been implicated [32].

Moreover, the roles of different T cell subsets in RA are becoming increasingly understood. T helper 1 (Th1) cells are known to produce pro-inflammatory cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which are critical for cartilage destruction and bone erosion [33]. Th17 cells secrete interleukin-22 (IL-22), promoting the proliferation of synovial fibroblasts and contributing to the inflammatory process [34]. Additionally, T follicular helper (Tfh) cells are essential for B cell activation and antibody production, further perpetuating the autoimmune response [34].

The complexity of T cell involvement in RA is further underscored by the emergence of unconventional T cell subsets, such as natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells, which also play significant roles in amplifying inflammatory responses and joint tissue destruction [35]. The interactions among these T cell subsets and their regulatory mechanisms highlight the intricate network of immune dysregulation in RA.

Overall, the mechanisms of RA are multifaceted, with T cells at the center of the autoimmune response. Their dysregulation, characterized by metabolic abnormalities, diverse functional roles, and interactions with other immune cells, contributes significantly to the pathogenesis of this debilitating disease. Understanding these mechanisms not only elucidates the underlying biology of RA but also opens avenues for targeted therapeutic interventions aimed at modulating T cell responses and restoring immune balance.

4.2 Contribution of B Cells and Antibody Production ​

Rheumatoid arthritis (RA) is characterized by chronic autoimmune dysregulation, leading to significant synovial inflammation, joint destruction, and associated disability. Central to the pathogenesis of RA is the contribution of B cells and the production of autoantibodies, which play multifaceted roles in disease progression.

B cells are pivotal in the immunopathogenesis of RA through various mechanisms. They are responsible for the production of rheumatoid factors and anti-citrullinated protein antibodies (ACPAs), which are crucial in forming immune complexes that exacerbate inflammation in the joints. These autoantibodies contribute to complement activation and leukocyte recruitment, amplifying the inflammatory response within the synovial tissue [36].

In addition to autoantibody production, B cells function as efficient antigen-presenting cells. They can activate T cells through the expression of costimulatory molecules and cytokines, thereby promoting further immune activation and perpetuating the inflammatory cycle [37]. The formation of ectopic lymphoid structures within the synovium, a process known as ectopic lymphoid neogenesis, is also significantly influenced by B cells. These structures facilitate local immune responses and are associated with disease severity [38].

Recent studies have highlighted the role of B cells beyond their antibody-producing capacity. B cells contribute to the production of pro-inflammatory cytokines and chemokines, which not only enhance leukocyte infiltration into the joints but also support synovial hyperplasia and angiogenesis [36]. Furthermore, B cells have been implicated in the modulation of T cell responses, suggesting a complex interplay between these immune cell types in the pathogenesis of RA [33].

The therapeutic efficacy of B cell depletion therapies, such as rituximab, underscores the critical role of B cells in RA. By targeting B cells, these therapies can disrupt multiple functions of B cells, leading to reduced disease activity and improved clinical outcomes [39]. However, the exact mechanisms by which B cell-targeted therapies exert their effects remain an area of active investigation, as it is essential to understand the specific roles of different B cell subpopulations in RA [40].

In summary, B cells contribute significantly to the pathogenesis of rheumatoid arthritis through autoantibody production, antigen presentation, cytokine release, and the formation of ectopic lymphoid structures. Understanding these mechanisms is crucial for developing targeted therapies aimed at restoring immune balance and improving patient outcomes in RA.

5 Cytokine Signaling and Inflammation ​

5.1 Pro-inflammatory Cytokines: IL-1, IL-6, and TNF-alpha ​

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovial joints, leading to progressive joint destruction and significant disability. Central to the pathogenesis of RA are pro-inflammatory cytokines, particularly interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). These cytokines play crucial roles in the induction and maintenance of inflammation, making them key therapeutic targets.

IL-1 is a pivotal pro-inflammatory cytokine that contributes significantly to the clinical manifestations of RA. It drives inflammation and joint erosion, while also inhibiting tissue repair processes. The activity of IL-1 is normally balanced by its natural antagonist, IL-1 receptor antagonist (IL-1Ra). However, in RA, the production of IL-1Ra is often insufficient to counteract the effects of IL-1, leading to enhanced inflammation and joint damage [41]. This imbalance is critical, as studies have shown that the administration of recombinant IL-1Ra can provide a new therapeutic modality for RA patients [41].

TNF-alpha is another key cytokine involved in RA. It is a major mediator of inflammation, with extensive evidence supporting its role in the disease process. Elevated levels of TNF-alpha are found in the synovial fluid of RA patients, and its neutralization has been shown to result in significant clinical benefits. For instance, clinical trials utilizing anti-TNF-alpha therapies have demonstrated marked improvements in symptoms and disease progression [42].

IL-6 is also recognized as a critical cytokine in RA, contributing to the inflammatory milieu. It is involved in various pathological processes, including the stimulation of acute phase reactants and the differentiation of B cells into antibody-producing cells. Elevated IL-6 levels have been associated with the severity of the disease, and targeting IL-6 has become a promising therapeutic strategy in RA management [43].

The interplay among these cytokines is complex. For instance, TNF-alpha not only promotes the production of IL-1 but also contributes to the secretion of IL-6 and other inflammatory mediators, creating a feedback loop that exacerbates inflammation [42]. This network of cytokines highlights the necessity for targeted therapies that can disrupt these pathways to mitigate joint destruction and improve patient outcomes.

In conclusion, the mechanisms underlying rheumatoid arthritis involve a complex interplay of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-alpha. Their roles in mediating inflammation and joint damage underscore the importance of these cytokines as therapeutic targets, paving the way for innovative treatment strategies aimed at restoring the balance between pro-inflammatory and anti-inflammatory signals in the rheumatoid joint [44][45][46].

5.2 Mechanisms of Synovial Inflammation ​

Rheumatoid arthritis (RA) is characterized by a complex interplay of immune responses leading to synovial inflammation, which is central to the pathogenesis of the disease. The mechanisms of synovial inflammation in RA involve various cellular components and signaling pathways, particularly the activation of inflammatory mediators, such as cytokines, chemokines, and growth factors.

The synovial tissue in RA is infiltrated by a variety of immune cells, including T lymphocytes, macrophages, and fibroblast-like synoviocytes (FLSs). These cells play a crucial role in the inflammatory process. For instance, FLSs are activated in the inflamed joints and are key drivers of the disease, contributing to the production of pro-inflammatory cytokines that sustain chronic joint inflammation and lead to tissue destruction [47].

Cytokines, particularly tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), are pivotal in mediating the inflammatory response. They promote the activation and proliferation of immune cells, as well as the production of additional inflammatory mediators, perpetuating a cycle of inflammation and joint damage [48]. Moreover, the interaction between T cells and synovial cells further exacerbates inflammation, with Th17 cells being implicated in the modulation of synovial tissue inflammation [47].

Angiogenesis, or the formation of new blood vessels, is another critical mechanism in RA, facilitating the infiltration of immune cells into the synovial tissue and contributing to the hypervascularization observed in inflamed joints [49]. This process is driven by the secretion of angiogenic factors by activated immune cells and FLSs, creating a microenvironment that supports chronic inflammation and joint destruction [50].

The local production of various cytokines within the inflamed synovium leads to the activation of metalloproteinases, which are enzymes that degrade extracellular matrix components, further contributing to joint damage [51]. Additionally, the presence of autoantibodies and immune complexes within the synovium can trigger complement activation, which also plays a role in sustaining the inflammatory response [50].

In summary, the mechanisms of synovial inflammation in rheumatoid arthritis are multifaceted, involving a range of immune cells and cytokines that drive the inflammatory process, leading to joint destruction and systemic manifestations. Understanding these mechanisms is essential for developing targeted therapeutic strategies to manage the disease effectively [52][53][54].

6 Joint Destruction Mechanisms ​

6.1 Osteoclast Activation and Bone Resorption ​

Rheumatoid arthritis (RA) is characterized by chronic inflammation leading to joint destruction, primarily mediated by osteoclasts, which are responsible for bone resorption. The mechanisms underlying osteoclast activation and subsequent bone resorption in RA involve a complex interplay between various immune cells, pro-inflammatory cytokines, and the bone microenvironment.

The activation of osteoclasts in RA is significantly influenced by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-17 (IL-17). These cytokines are secreted by infiltrating immune cells, including T cells, B cells, and macrophages, as well as resident synovial cells. They play a critical role in promoting osteoclastogenesis by enhancing the expression of receptor activator of nuclear factor-κB ligand (RANKL), a key factor that stimulates the differentiation and activation of osteoclasts from their precursors [55][56][57].

In the context of RA, autoantibodies, particularly rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), have been shown to exert effector functions that facilitate osteoclast activation. These autoantibodies can directly stimulate osteoclastogenesis and enhance the resorptive activity of osteoclasts, thereby contributing to bone loss [58][59].

The interaction between immune cells and synovial fibroblasts is also crucial in the pathogenesis of bone destruction in RA. Synovial fibroblasts, when activated by pro-inflammatory cytokines, can produce RANKL and other factors that further promote osteoclast differentiation. This creates a feedback loop that exacerbates bone resorption [57][60].

Additionally, the balance between osteoclasts and osteoblasts is disrupted in RA. While osteoclasts are activated and increase bone resorption, the activity of osteoblasts, which are responsible for bone formation, is inhibited by inflammatory cytokines. This imbalance leads to a net loss of bone, manifesting as local erosions and systemic osteoporosis [55][57].

Recent advancements in understanding the molecular pathways involved in osteoclast activation have highlighted the importance of signaling molecules such as NF-κB, MAPK, and NFATc1, which are activated during osteoclastogenesis. Targeting these pathways offers potential therapeutic strategies to mitigate bone destruction in RA [61][62].

In summary, the mechanisms of osteoclast activation and bone resorption in rheumatoid arthritis are multifaceted, involving pro-inflammatory cytokines, autoantibodies, and the interactions between various immune and bone cells. This understanding underscores the importance of developing targeted therapies that can effectively interrupt these pathways to prevent or reduce bone loss in RA patients.

6.2 Cartilage Degradation Processes ​

Rheumatoid arthritis (RA) is characterized by the destruction of joint cartilage and underlying bone, which is a significant consequence of the disease. The mechanisms underlying cartilage degradation in RA are complex and involve various cellular and molecular pathways.

Cartilage destruction in RA primarily occurs due to proteolysis mediated by enzymes known as metalloproteinases (MMPs). The production and expression of MMPs are regulated by a variety of local mediators, including cytokines, growth factors, prostaglandins, oxygen species, and neuropeptides. Notably, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNFα) play crucial roles in MMP activation. When these cytokines bind to their respective membrane receptors, they initiate signaling cascades that activate downstream pathways, including TGF-beta-activating kinase (TAK-1), NF-kappaB, and mitogen-activated protein kinases (MAP kinases), ultimately leading to the activation of transcription factors like activator protein-1 (AP-1) (Rannou et al. 2006) [63].

In addition to MMPs, the presence of pro-inflammatory cytokines disrupts the normal homeostasis of cartilage by impairing the repair mechanisms mediated by chondrocytes and osteoblasts. This disruption is compounded by the infiltration of immune cells and the inflammatory milieu that develops in the affected joints, further enhancing the activity of osteoclasts, the cells responsible for bone resorption (Harre and Schett 2017) [62].

Chondrocytes, the primary cells of cartilage, are also implicated in the degradation process. The inflammatory environment influences chondrocyte function, leading to their transformation into a phenotype that contributes to cartilage destruction. This includes increased production of inflammatory mediators and enzymes that degrade the extracellular matrix (Otero and Goldring 2007) [64].

The role of oxidative stress in cartilage degradation has also been highlighted, with reactive oxygen species (ROS) being generated during inflammatory conditions. These ROS can react with various cartilage components, exacerbating degradation and inflammation within the joint (Schiller et al. 2003) [65].

Moreover, the balance between cartilage degradation and regeneration is disrupted in RA. The cytokine network perpetuates joint destruction by directly regulating metalloproteases and indirectly recruiting cells that secrete degradative enzymes, while simultaneously inhibiting reparative processes (Sipe et al. 1994) [66].

In summary, the mechanisms of cartilage degradation in rheumatoid arthritis involve a complex interplay of inflammatory cytokines, MMPs, chondrocyte activity, oxidative stress, and a dysregulated balance between degradation and repair processes. Understanding these mechanisms is critical for developing targeted therapies aimed at halting or reversing joint destruction in RA.

7 Conclusion ​

The mechanisms underlying rheumatoid arthritis (RA) are multifaceted, involving a complex interplay of genetic, environmental, and immunological factors that contribute to the disease's pathogenesis. Genetic predisposition, particularly the role of the HLA-DRB1 gene and various susceptibility loci, has been established as a critical component influencing individual risk. Environmental triggers, such as smoking and infectious agents, further exacerbate susceptibility and disease progression, highlighting the significance of gene-environment interactions. The dysregulation of the immune system, particularly the roles of T cells and B cells, is central to the inflammatory processes observed in RA. Pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, sustain synovial inflammation and joint destruction, while mechanisms of osteoclast activation and cartilage degradation underscore the devastating effects of the disease on joint integrity. Future research should focus on elucidating the remaining gaps in our understanding of RA pathogenesis, exploring novel therapeutic targets, and improving treatment strategies to enhance patient outcomes. Advances in precision medicine, aimed at tailoring interventions based on individual genetic and environmental profiles, may hold promise for more effective management of RA.

References ​

  • [1] Uzma Saleem;Maryam Farrukh;Malik Saadullah;Rida Siddique;Humaira Gul;Aqsa Ahmad;Bushra Shaukat;Muhammad Ajmal Shah. Role of polyphenolics in the management of rheumatoid arthritis through intracellular signaling pathways: a mechanistic review.. Inflammopharmacology(IF=5.3). 2025. PMID:40220198. DOI: 10.1007/s10787-025-01731-z.
  • [2] Bryant R England;Geoffrey M Thiele;Daniel R Anderson;Ted R Mikuls. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications.. BMJ (Clinical research ed.)(IF=42.7). 2018. PMID:29685876. DOI: 10.1136/bmj.k1036.
  • [3] Tapan Behl;Swati Chadha;Monika Sachdeva;Arun Kumar;Abdul Hafeez;Vineet Mehta;Simona Bungau. Ubiquitination in rheumatoid arthritis.. Life sciences(IF=5.1). 2020. PMID:32961230. DOI: 10.1016/j.lfs.2020.118459.
  • [4] Tao Wang;Zhandong Wang;Wenxia Qi;Ganggang Jiang;Gang Wang. Possible Future Avenues for Rheumatoid Arthritis Therapeutics: Hippo Pathway.. Journal of inflammation research(IF=4.1). 2023. PMID:36998323. DOI: 10.2147/JIR.S403925.
  • [5] Marie-Christophe Boissier;Jérome Biton;Luca Semerano;Patrice Decker;Natacha Bessis. Origins of rheumatoid arthritis.. Joint bone spine(IF=4.3). 2020. PMID:31812725. DOI: 10.1016/j.jbspin.2019.11.009.
  • [6] Jangampalli Adi Pradeepkiran. Insights of rheumatoid arthritis risk factors and associations.. Journal of translational autoimmunity(IF=3.6). 2019. PMID:32743500. DOI: 10.1016/j.jtauto.2019.100012.
  • [7] Rene E M Toes. The Autoantibody response in rheumatoid arthritis; what makes it unique?. Seminars in arthritis and rheumatism(IF=4.4). 2025. PMID:40044517. DOI: 10.1016/j.semarthrit.2025.152699.
  • [8] Xiaoou Ye;Dan Ren;Qingyuan Chen;Jiquan Shen;Bo Wang;Songquan Wu;Hongliang Zhang. Resolution of inflammation during rheumatoid arthritis.. Frontiers in cell and developmental biology(IF=4.3). 2025. PMID:40206402. DOI: 10.3389/fcell.2025.1556359.
  • [9] Mahendra Kumar Verma;Kota Sobha. Understanding the major risk factors in the beginning and the progression of rheumatoid arthritis: current scenario and future prospects.. Inflammation research : official journal of the European Histamine Research Society ... et al.. 2015. PMID:26149692. DOI: 10.1007/s00011-015-0843-8.
  • [10] Tibor T Glant;Katalin Mikecz;Tibor A Rauch. Epigenetics in the pathogenesis of rheumatoid arthritis.. BMC medicine(IF=8.3). 2014. PMID:24568138. DOI: 10.1186/1741-7015-12-35.
  • [11] Carlo Perricone;Fulvia Ceccarelli;Guido Valesini. An overview on the genetic of rheumatoid arthritis: a never-ending story.. Autoimmunity reviews(IF=8.3). 2011. PMID:21545847. DOI: 10.1016/j.autrev.2011.04.021.
  • [12] Claire Gorman;Timothy Vyse;Andrew Cope. What does the immunogenetic basis of rheumatoid arthritis teach us about the immunobiology of the disease?. Expert review of clinical immunology(IF=3.7). 2006. PMID:20477627. DOI: 10.1586/1744666X.2.5.717.
  • [13] Diego Kyburz;Emmanuel Karouzakis;Caroline Ospelt. Epigenetic changes: the missing link.. Best practice & research. Clinical rheumatology(IF=4.8). 2014. PMID:25481551. DOI: .
  • [14] Dmitry S Mikhaylenko;Marina V Nemtsova;Irina V Bure;Ekaterina B Kuznetsova;Ekaterina A Alekseeva;Vadim V Tarasov;Alexander N Lukashev;Marina I Beloukhova;Andrei A Deviatkin;Andrey A Zamyatnin. Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response.. International journal of molecular sciences(IF=4.9). 2020. PMID:32664585. DOI: 10.3390/ijms21144911.
  • [15] A L Feitsma;A H M van der Helm-van Mil;T W J Huizinga;R R P de Vries;R E M Toes. Protection against rheumatoid arthritis by HLA: nature and nurture.. Annals of the rheumatic diseases(IF=20.6). 2008. PMID:19022816. DOI: 10.1136/ard.2008.098509.
  • [16] Damini Jawaheer;Wentian Li;Robert R Graham;Wei Chen;Aarti Damle;Xiangli Xiao;Joanita Monteiro;Houman Khalili;Annette Lee;Robert Lundsten;Ann Begovich;Teodorica Bugawan;Henry Erlich;James T Elder;Lindsey A Criswell;Michael F Seldin;Christopher I Amos;Timothy W Behrens;Peter K Gregersen. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.. American journal of human genetics(IF=8.1). 2002. PMID:12181776. DOI: 10.1086/342407.
  • [17] G Orozco;B Rueda;J Martin. Genetic basis of rheumatoid arthritis.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(IF=7.5). 2006. PMID:17055211. DOI: 10.1016/j.biopha.2006.09.003.
  • [18] Chikashi Terao;Soumya Raychaudhuri;Peter K Gregersen. Recent Advances in Defining the Genetic Basis of Rheumatoid Arthritis.. Annual review of genomics and human genetics(IF=7.9). 2016. PMID:27216775. DOI: 10.1146/annurev-genom-090314-045919.
  • [19] A Krause;T Kamradt;G R Burmester. Potential infectious agents in the induction of arthritides.. Current opinion in rheumatology(IF=4.3). 1996. PMID:8796979. DOI: 10.1097/00002281-199605000-00007.
  • [20] Emanuele Calabresi;Fiorella Petrelli;Angelo Francesco Bonifacio;Ilaria Puxeddu;Alessia Alunno. One year in review 2018: pathogenesis of rheumatoid arthritis.. Clinical and experimental rheumatology(IF=3.3). 2018. PMID:29716677. DOI: .
  • [21] Marina I Arleevskaya;Olga A Kravtsova;Julie Lemerle;Yves Renaudineau;Anatoly P Tsibulkin. How Rheumatoid Arthritis Can Result from Provocation of the Immune System by Microorganisms and Viruses.. Frontiers in microbiology(IF=4.5). 2016. PMID:27582741. DOI: 10.3389/fmicb.2016.01296.
  • [22] Malavikalakshmi Attur;Jose U Scher;Steven B Abramson;Mukundan Attur. Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis.. Cells(IF=5.2). 2022. PMID:35954278. DOI: 10.3390/cells11152436.
  • [23] Kathleen Chang;So Min Yang;Seong Heon Kim;Kyoung Hee Han;Se Jin Park;Jae Il Shin. Smoking and rheumatoid arthritis.. International journal of molecular sciences(IF=4.9). 2014. PMID:25479074. DOI: 10.3390/ijms151222279.
  • [24] Yuki Ishikawa;Chikashi Terao. The Impact of Cigarette Smoking on Risk of Rheumatoid Arthritis: A Narrative Review.. Cells(IF=5.2). 2020. PMID:32092988. DOI: 10.3390/cells9020475.
  • [25] L Klareskog;L Alfredsson;S Rantapää-Dahlqvist;E Berglin;P Stolt;L Padyukov. What precedes development of rheumatoid arthritis?. Annals of the rheumatic diseases(IF=20.6). 2004. PMID:15479868. DOI: 10.1136/ard.2004.028225.
  • [26] I C Scott;S Steer;C M Lewis;A P Cope. Precipitating and perpetuating factors of rheumatoid arthritis immunopathology: linking the triad of genetic predisposition, environmental risk factors and autoimmunity to disease pathogenesis.. Best practice & research. Clinical rheumatology(IF=4.8). 2011. PMID:22137917. DOI: 10.1016/j.berh.2011.10.010.
  • [27] Ryan A Hoovestol;Ted R Mikuls. Environmental exposures and rheumatoid arthritis risk.. Current rheumatology reports(IF=3.9). 2011. PMID:21785978. DOI: 10.1007/s11926-011-0203-9.
  • [28] Courtney Lynn Marshall;Mahadevappa Hemshekhar;Neeloffer Mookherjee;Liam J O'Neil. Where there's smoke, there's fire: insights from murine models on the effect of cigarette smoke in rheumatoid arthritis development.. Frontiers in immunology(IF=5.9). 2025. PMID:40463383. DOI: 10.3389/fimmu.2025.1588419.
  • [29] Jeba Atkia Maisha;Hani S El-Gabalawy;Liam J O'Neil. Modifiable risk factors linked to the development of rheumatoid arthritis: evidence, immunological mechanisms and prevention.. Frontiers in immunology(IF=5.9). 2023. PMID:37767100. DOI: 10.3389/fimmu.2023.1221125.
  • [30] J Dudler;A K So. T cells and related cytokines.. Current opinion in rheumatology(IF=4.3). 1998. PMID:9608323. DOI: 10.1097/00002281-199805000-00009.
  • [31] Mingyue Hu;Yujun Zhou;Zhongliu Yao;Yuanyuan Tang;Ye Zhang;Jing Liao;Xiong Cai;Liang Liu. T cell dysregulation in rheumatoid arthritis: Recent advances and natural product interventions.. International immunopharmacology(IF=4.7). 2025. PMID:40120382. DOI: 10.1016/j.intimp.2025.114499.
  • [32] Asmita Parab;Lokesh Kumar Bhatt. T-cell metabolism in rheumatoid arthritis: focus on mitochondrial and lysosomal dysfunction.. Immunopharmacology and immunotoxicology(IF=3.0). 2024. PMID:38478010. DOI: 10.1080/08923973.2024.2330645.
  • [33] Byeongzu Ghang;Jin Kyun Park;Ji Hyeon Ju;Seungwoo Han. Current state and future directions of basic research in rheumatoid arthritis.. Journal of rheumatic diseases(IF=3.0). 2025. PMID:40584767. DOI: 10.4078/jrd.2024.0151.
  • [34] Pan Luo;Peixu Wang;Jiawen Xu;Weikun Hou;Peng Xu;Ke Xu;Lin Liu. Immunomodulatory role of T helper cells in rheumatoid arthritis : a comprehensive research review.. Bone & joint research(IF=5.1). 2022. PMID:35775145. DOI: 10.1302/2046-3758.117.BJR-2021-0594.R1.
  • [35] Tangqing Xu;Hao Cai;Jianye Liu;Xingxing Mao;Yulong Chen;Minhao Chen;Youhua Wang. Exploring the role of unconventional T cells in rheumatoid arthritis.. Frontiers in immunology(IF=5.9). 2025. PMID:40909276. DOI: 10.3389/fimmu.2025.1656994.
  • [36] Gregg J Silverman;Dennis A Carson. Roles of B cells in rheumatoid arthritis.. Arthritis research & therapy(IF=4.6). 2003. PMID:15180890. DOI: 10.1186/ar1010.
  • [37] Claudia Mauri;Michael R Ehrenstein. Cells of the synovium in rheumatoid arthritis. B cells.. Arthritis research & therapy(IF=4.6). 2007. PMID:17349064. DOI: 10.1186/ar2125.
  • [38] Cornelia M Weyand;Thorsten M Seyler;Jörg J Goronzy. B cells in rheumatoid synovitis.. Arthritis research & therapy(IF=4.6). 2005. PMID:15960820. DOI: 10.1186/ar1737.
  • [39] Anuja Singh;Tapan Behl;Aayush Sehgal;Sukhbir Singh;Neelam Sharma;Tanveer Naved;Saurabh Bhatia;Ahmed Al-Harrasi;Prasun Chakrabarti;Lotfi Aleya;Celia Vargas-De-La-Cruz;Simona Bungau. Mechanistic insights into the role of B cells in rheumatoid arthritis.. International immunopharmacology(IF=4.7). 2021. PMID:34426116. DOI: 10.1016/j.intimp.2021.108078.
  • [40] Yongqi Liang;Menglei Zha;Qifeng Liu;Zhifei Lai;Lei Li;Yiming Shao;Jianbo Sun. Rheumatoid Arthritis Therapy Based on B Cells.. Drug design, development and therapy(IF=5.1). 2025. PMID:40951695. DOI: 10.2147/DDDT.S527687.
  • [41] J M Dayer. The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis.. Rheumatology (Oxford, England)(IF=4.4). 2003. PMID:12817089. DOI: 10.1093/rheumatology/keg326.
  • [42] M Feldmann;F M Brennan;R N Maini. Role of cytokines in rheumatoid arthritis.. Annual review of immunology(IF=33.3). 1996. PMID:8717520. DOI: 10.1146/annurev.immunol.14.1.397.
  • [43] G Carroll;M Bell;H Wang;H Chapman;J Mills. Antagonism of the IL-6 cytokine subfamily--a potential strategy for more effective therapy in rheumatoid arthritis.. Inflammation research : official journal of the European Histamine Research Society ... et al.. 1998. PMID:9495579. DOI: 10.1007/s000110050235.
  • [44] Cem Gabay. Cytokine inhibitors in the treatment of rheumatoid arthritis.. Expert opinion on biological therapy(IF=4.0). 2002. PMID:11849114. DOI: 10.1517/14712598.2.2.135.
  • [45] Mélissa Noack;Pierre Miossec. Selected cytokine pathways in rheumatoid arthritis.. Seminars in immunopathology(IF=9.2). 2017. PMID:28213794. DOI: 10.1007/s00281-017-0619-z.
  • [46] C Christodoulou;E H Choy. Joint inflammation and cytokine inhibition in rheumatoid arthritis.. Clinical and experimental medicine(IF=3.5). 2006. PMID:16550339. DOI: 10.1007/s10238-006-0088-5.
  • [47] Yusuke Takeuchi;Keiji Hirota;Shimon Sakaguchi. Synovial Tissue Inflammation Mediated by Autoimmune T Cells.. Frontiers in immunology(IF=5.9). 2019. PMID:31497022. DOI: 10.3389/fimmu.2019.01989.
  • [48] B Combe. [Inflammation and joint destruction during rheumatoid polyarthritis: what relation?].. Presse medicale (Paris, France : 1983)(IF=3.4). 1998. PMID:9767983. DOI: .
  • [49] Megan M Hanlon;Mary Canavan;Brianne E Barker;Ursula Fearon. Metabolites as drivers and targets in rheumatoid arthritis.. Clinical and experimental immunology(IF=3.8). 2022. PMID:35020864. DOI: 10.1093/cei/uxab021.
  • [50] J J Cush;P E Lipsky. Cellular basis for rheumatoid inflammation.. Clinical orthopaedics and related research(IF=4.4). 1991. PMID:2009681. DOI: .
  • [51] G S Firestein. Mechanisms of tissue destruction and cellular activation in rheumatoid arthritis.. Current opinion in rheumatology(IF=4.3). 1992. PMID:1599815. DOI: 10.1097/00002281-199206000-00012.
  • [52] Felice Rivellese;Costantino Pitzalis. Cellular and molecular diversity in Rheumatoid Arthritis.. Seminars in immunology(IF=7.8). 2021. PMID:35033462. DOI: 10.1016/j.smim.2021.101519.
  • [53] Z Szekanecz;A E Koch. Update on synovitis.. Current rheumatology reports(IF=3.9). 2001. PMID:11177771. DOI: 10.1007/s11926-001-0051-0.
  • [54] Hans P Kiener;Thomas Karonitsch. The synovium as a privileged site in rheumatoid arthritis: cadherin-11 as a dominant player in synovial pathology.. Best practice & research. Clinical rheumatology(IF=4.8). 2011. PMID:22265259. DOI: 10.1016/j.berh.2011.11.012.
  • [55] Tobias Braun;Jochen Zwerina. Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis.. Arthritis research & therapy(IF=4.6). 2011. PMID:21861862. DOI: 10.1186/ar3380.
  • [56] Nicola Maruotti;Maria Grano;Silvia Colucci;Francesca d'Onofrio;Francesco Paolo Cantatore. Osteoclastogenesis and arthritis.. Clinical and experimental medicine(IF=3.5). 2011. PMID:21069419. DOI: 10.1007/s10238-010-0117-2.
  • [57] Fabienne Coury;Olivier Peyruchaud;Irma Machuca-Gayet. Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases.. Frontiers in immunology(IF=5.9). 2019. PMID:31001277. DOI: 10.3389/fimmu.2019.00679.
  • [58] Ulrike Steffen;Georg Schett;Aline Bozec. How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis.. Frontiers in immunology(IF=5.9). 2019. PMID:31333647. DOI: 10.3389/fimmu.2019.01483.
  • [59] Mélanie Auréal;Irma Machuca-Gayet;Fabienne Coury. Rheumatoid Arthritis in the View of Osteoimmunology.. Biomolecules(IF=4.8). 2020. PMID:33396412. DOI: 10.3390/biom11010048.
  • [60] Noriko Komatsu;Hiroshi Takayanagi. Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions.. Nature reviews. Rheumatology(IF=32.7). 2022. PMID:35705856. DOI: 10.1038/s41584-022-00793-5.
  • [61] Qinghua Fang;Chun Zhou;Kutty Selva Nandakumar. Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis.. Mediators of inflammation(IF=4.2). 2020. PMID:32256192. DOI: 10.1155/2020/3830212.
  • [62] Ulrike Harre;Georg Schett. Cellular and molecular pathways of structural damage in rheumatoid arthritis.. Seminars in immunopathology(IF=9.2). 2017. PMID:28597065. DOI: 10.1007/s00281-017-0634-0.
  • [63] François Rannou;Mathias François;Marie-Thérèse Corvol;Francis Berenbaum. Cartilage breakdown in rheumatoid arthritis.. Joint bone spine(IF=4.3). 2006. PMID:16087381. DOI: 10.1016/j.jbspin.2004.12.013.
  • [64] Miguel Otero;Mary B Goldring. Cells of the synovium in rheumatoid arthritis. Chondrocytes.. Arthritis research & therapy(IF=4.6). 2007. PMID:18001488. DOI: 10.1186/ar2292.
  • [65] J Schiller;B Fuchs;J Arnhold;K Arnold. Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.. Current medicinal chemistry(IF=3.5). 2003. PMID:12871089. DOI: 10.2174/0929867033456828.
  • [66] J D Sipe;J Martel-Pelletier;I G Otterness;J P Pelletier. Cytokine reduction in the treatment of joint conditions.. Mediators of inflammation(IF=4.2). 1994. PMID:18472950. DOI: 10.1155/S0962935194000359.

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