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

What are the mechanisms of osteoarthritis? ​

Abstract ​

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the progressive degradation of articular cartilage, subchondral bone remodeling, and synovial inflammation, affecting millions globally and posing significant public health challenges. The complexity of OA arises from its multifactorial etiology, including genetic predispositions, mechanical stress, biochemical changes, and environmental factors. Recent studies emphasize the critical role of various cellular and molecular pathways in OA pathogenesis, such as mitochondrial dysfunction leading to chondrocyte apoptosis and the interplay between inflammation and mechanical loading activating pro-inflammatory signaling pathways. This review systematically explores the pathophysiological mechanisms underlying OA, focusing on cartilage degradation, subchondral bone changes, and synovial inflammation, as well as genetic and molecular mechanisms, mechanical factors, and systemic influences like obesity. Advances in imaging techniques and potential biomarkers for early detection are also discussed. By synthesizing existing literature, this review aims to enhance understanding of OA mechanisms and identify therapeutic targets for improved management of this debilitating disease.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Pathophysiology of Osteoarthritis
    • 2.1 Cartilage Degradation
    • 2.2 Subchondral Bone Changes
    • 2.3 Synovial Inflammation
  • 3 Genetic and Molecular Mechanisms
    • 3.1 Genetic Predisposition
    • 3.2 Molecular Pathways Involved in OA
  • 4 Role of Mechanical Factors
    • 4.1 Joint Loading and Biomechanics
    • 4.2 Impact of Physical Activity
  • 5 Systemic Factors Influencing Osteoarthritis
    • 5.1 Obesity and Metabolic Syndrome
    • 5.2 Inflammatory Markers and Systemic Conditions
  • 6 Advances in Imaging and Biomarkers
    • 6.1 Imaging Techniques for OA Assessment
    • 6.2 Potential Biomarkers for Early Detection
  • 7 Summary

1 Introduction ​

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the progressive degradation of articular cartilage, subchondral bone remodeling, and synovial inflammation. It is estimated that millions of individuals worldwide are affected by OA, making it one of the most common forms of arthritis and a significant public health concern. The disease not only leads to chronic pain and functional impairment but also imposes substantial economic burdens on healthcare systems due to its associated disability and treatment costs [1][2]. Understanding the underlying mechanisms of OA is essential for the development of effective therapeutic strategies aimed at improving patient outcomes.

The complexity of OA arises from its multifactorial etiology, which includes genetic predispositions, mechanical stress, biochemical changes, and environmental factors [2]. Recent studies have highlighted the importance of various cellular and molecular pathways in the pathogenesis of OA. For instance, the role of mitochondrial dysfunction has emerged as a critical factor contributing to chondrocyte apoptosis and oxidative stress, which in turn exacerbates cartilage degradation [3]. Furthermore, the interplay between inflammation and the mechanical loading of joints has been shown to activate pro-inflammatory signaling pathways, further complicating the disease process [4].

Current research emphasizes a shift in perspective from viewing OA solely as a disease of cartilage to recognizing it as a disorder of the entire joint, involving not only the cartilage but also the synovium and subchondral bone [2]. This holistic approach underscores the necessity for a comprehensive understanding of the interrelated mechanisms driving OA progression. For example, damage-associated molecular patterns (DAMPs) released during joint injury can activate the immune response, leading to chronic inflammation and further joint damage [1]. Moreover, the emerging concept of the "gut-joint axis" suggests that gut microbiota may influence the pathophysiology of OA through metabolic and immune-mediated pathways [5].

This review will systematically explore the pathophysiological mechanisms underlying OA, focusing on several key aspects: (1) the processes of cartilage degradation, subchondral bone changes, and synovial inflammation; (2) genetic and molecular mechanisms, including genetic predisposition and relevant molecular pathways; (3) the role of mechanical factors, such as joint loading and physical activity; (4) systemic factors influencing OA, particularly obesity and metabolic syndrome; and (5) recent advances in imaging techniques and potential biomarkers for early detection and monitoring of OA [2][6].

The first section will provide an overview of the pathophysiology of OA, detailing the mechanisms of cartilage degradation, changes in subchondral bone, and the role of synovial inflammation. The subsequent sections will delve into genetic factors and molecular pathways that contribute to OA, as well as the impact of mechanical and systemic factors on disease progression. Finally, we will discuss the latest advances in imaging and biomarker research that hold promise for improving the diagnosis and management of OA.

By synthesizing existing literature and highlighting key areas for future research, this review aims to contribute to a deeper understanding of the complex mechanisms of OA and to identify potential therapeutic targets that may improve the management of this debilitating disease.

2 Pathophysiology of Osteoarthritis ​

2.1 Cartilage Degradation ​

Osteoarthritis (OA) is characterized by a complex interplay of mechanisms leading to cartilage degradation, which is central to its pathophysiology. The pathogenesis of OA involves various factors, including mechanical, biochemical, and cellular changes that collectively contribute to the degradation of articular cartilage.

The degradation of cartilage in OA is primarily driven by the activity of matrix metalloproteinases (MMPs), which are enzymes that degrade the extracellular matrix (ECM) components. According to Howell (1986), the degradation process is initiated by diffuse or focal exposure of the ECM to active neutral metalloproteinases, resulting in injury and the initiation of repair processes. This exposure is often a pathological consequence of physical injury to local chondrocytes or inflammatory mediators rather than a physiological aberration[7].

Recent research by Abramson and Attur (2009) emphasizes the shift in understanding OA from merely a disease of cartilage to one that affects the "whole joint," where the synovium, bone, and cartilage are involved in pathological processes. This broadening perspective highlights the role of inflammation and the importance of biomechanical factors in the progression of cartilage degradation[4].

Chondrocyte apoptosis plays a significant role in cartilage degeneration. Kong et al. (2024) describe how the loss or dysfunction of chondrocytes, the sole resident cells responsible for producing ECM proteins, leads to progressive cartilage deterioration. Apoptosis in chondrocytes is correlated with cartilage degradation, yet the specific causes of this apoptosis remain poorly understood. Autophagy, an intracellular process that helps eliminate dysfunctional components, has been identified as a potential therapeutic target to inhibit chondrocyte apoptosis and mitigate OA severity[8].

Additionally, genetic and epigenetic factors are increasingly recognized as contributing to OA pathogenesis. Kiełbowski et al. (2023) discuss how pro-inflammatory immune mediators regulate metalloproteinase expression, which is crucial for cartilage degradation. Genetic predispositions, along with epigenetic modifications, can influence the expression of genes associated with OA, thereby affecting individual susceptibility to the disease[9].

Mechanical factors also play a critical role in the degradation of cartilage. Vincent and Wann (2019) note that articular cartilage is highly sensitive to mechanical load, and abnormal mechanical conditions can lead to cartilage destruction. The physiological interactions between bone and cartilage are essential for maintaining joint integrity, and an imbalance in these interactions can lead to increased cartilage catabolism[10].

In summary, the mechanisms underlying cartilage degradation in osteoarthritis are multifaceted, involving the actions of metalloproteinases, chondrocyte apoptosis, genetic and epigenetic factors, and mechanical influences. These interconnected pathways highlight the complexity of OA and the need for comprehensive approaches to treatment that address these various aspects of the disease.

2.2 Subchondral Bone Changes ​

Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage and alterations in subchondral bone. The pathophysiology of OA involves a complex interplay of mechanical, biochemical, and cellular processes that lead to structural changes in both cartilage and subchondral bone.

The subchondral bone plays a pivotal role in the development and progression of OA. Initially, subchondral bone changes are not merely secondary manifestations of cartilage degeneration but are integral to the disease process. Research indicates that alterations in the subchondral bone occur early in OA, often preceding detectable cartilage damage. For instance, Goldring (2012) highlights that the composition, structure, and functional properties of subchondral bone are altered due to both biomechanical and biological processes, which directly affect the overlying articular cartilage [11].

One of the primary mechanisms involves increased bone remodeling in response to abnormal mechanical stress and loading conditions. In early OA, there is a shift towards increased bone resorption, followed by a phase of increased bone formation, leading to higher bone density and subsequent sclerosis of the subchondral bone [12]. This remodeling process is driven by various cell types, including osteoblasts, osteocytes, and osteoclasts, which are crucial in maintaining the balance of bone formation and resorption [13].

The pathophysiological changes in subchondral bone include increased thickness of the subchondral cortical bone, reduced trabecular bone mass, and the formation of marginal osteophytes [11]. These changes can lead to microfractures and bone marrow lesions, which are indicative of ongoing bone remodeling and stress response [14]. Moreover, the development of subchondral bone cysts and the expansion of the calcified cartilage zone contribute to the thinning of articular cartilage [11].

Another critical aspect is the biochemical environment within the subchondral bone, which can become altered during OA. Increased collagen metabolism and hypomineralization of the subchondral bone have been observed, indicating a shift in the matrix composition that may exacerbate joint deterioration [15]. The interplay between subchondral bone and articular cartilage is further complicated by the release of soluble mediators from chondrocytes, which can influence the remodeling processes in the bone [11].

Additionally, the role of the autonomic nervous system (ANS) in regulating bone remodeling processes during OA has garnered attention. The sympathetic and parasympathetic nervous systems may influence the physiological changes in subchondral bone, potentially offering new therapeutic targets [12].

In summary, the mechanisms of osteoarthritis, particularly concerning subchondral bone changes, encompass a range of biological and mechanical factors. These include alterations in bone remodeling dynamics, changes in bone microarchitecture, and the biochemical environment, all of which contribute to the progression of OA and its associated symptoms. Understanding these mechanisms is crucial for developing targeted therapeutic strategies aimed at mitigating the effects of OA on joint health.

2.3 Synovial Inflammation ​

Osteoarthritis (OA) is characterized by a complex interplay of various biological mechanisms, with synovial inflammation playing a crucial role in its pathophysiology. Research indicates that OA is not merely a degenerative disease affecting cartilage but rather a systemic musculoskeletal disorder that involves inflammation of the synovium and other joint tissues. This inflammation is often termed synovitis, which is associated with significant histological changes and clinical manifestations.

The synovial membrane in OA exhibits alterations such as hyperplasia, infiltration of immune cells like macrophages and lymphocytes, neoangiogenesis, and fibrosis. These changes contribute to the production of pro-inflammatory cytokines and other mediators that exacerbate cartilage degradation and joint dysfunction (Scanzello and Goldring, 2012; Henrotin et al., 2014). Specifically, the inflammatory response in the synovium is triggered by various factors, including damage-associated molecular patterns from degraded cartilage and other joint tissues, which activate synovial cells through pathways involving Toll-like receptors and the complement cascade (Sanchez-Lopez et al., 2022).

Furthermore, synovial inflammation is linked to increased vascularity in the synovial membrane, which facilitates the infiltration of immune cells and perpetuates the inflammatory cycle. This angiogenesis is a critical feature that not only supports inflammation but also contributes to the chronicity of the disease (Henrotin et al., 2014). As the inflammation progresses, it can lead to pain sensitization and functional impairment in patients, with studies showing that synovitis correlates with more severe symptoms and faster rates of cartilage loss (Scanzello, 2017).

Recent findings also highlight the role of specific inflammatory mediators, including cytokines and chemokines, in the pathogenesis of OA. These mediators can have catabolic effects on chondrocytes, promoting cartilage breakdown (Malemud, 2015). In addition, synovial macrophages have been identified as key players in the inflammatory response, interacting with nociceptive neurons and contributing to pain perception in OA (Wang et al., 2022).

The understanding of synovial inflammation in OA has led to the exploration of targeted therapeutic strategies aimed at modulating this inflammatory response. Approaches that focus on inhibiting specific inflammatory pathways or cytokines hold promise for alleviating symptoms and potentially modifying disease progression (Mathiessen and Conaghan, 2017).

In summary, the pathophysiology of osteoarthritis is significantly influenced by synovial inflammation, characterized by a complex network of immune cell interactions, cytokine production, and structural changes in the joint. This inflammation not only contributes to the clinical symptoms of OA but also plays a pivotal role in the progression of cartilage degeneration and joint dysfunction.

3 Genetic and Molecular Mechanisms ​

3.1 Genetic Predisposition ​

Osteoarthritis (OA) is a complex and multifactorial disease characterized by the degeneration of articular cartilage, subchondral bone remodeling, and synovial inflammation. Genetic predisposition plays a significant role in the pathogenesis of OA, with genetic variation estimated to contribute to approximately 50% of the disease occurrence. Recent advances in genetic research, particularly through genome-wide association studies (GWAS), have identified over 300 genomic loci associated with OA, revealing a significant heritable component to the disease [16].

The genetic mechanisms underlying OA are diverse and involve multiple genes that regulate various biological pathways. Many of the identified genetic risk variants map to non-protein coding regions of the genome, suggesting that they may influence the expression of nearby genes rather than coding for proteins directly. This implies that epigenetic factors, such as DNA methylation changes, may serve as a conduit through which genetic effects on gene expression are mediated [17].

Several specific genes have been implicated in OA susceptibility. For instance, the interleukin 1 gene (IL1) cluster, the matrilin 3 gene (MATN3), and the asporin gene (ASPN) are among those that have been convincingly associated with OA [18]. These genes are involved in regulating cartilage chondrocyte differentiation and survival, which are critical processes in maintaining cartilage homeostasis. Additionally, genetic studies have indicated that some of the OA-associated genes, such as GDF5 and DIO2, are linked to pathways involved in joint and bone biology, as well as inflammatory responses [19].

The interplay between genetic predisposition and environmental factors, such as obesity and mechanical load, further complicates the etiology of OA. It has been suggested that genetic variants may also reflect adaptations related to bipedalism, where certain alleles may confer advantages in joint formation but pose risks for long-term joint health [17].

Epigenetic modifications, including DNA methylation, histone modifications, and microRNA activity, are crucial in the regulation of gene expression related to OA. These epigenetic changes can occur in response to environmental stimuli and may be inherited during cell division, thus influencing the disease progression [20]. For example, alterations in the expression of metalloproteinases, which are involved in cartilage degradation, can be regulated by these epigenetic mechanisms [21].

In summary, the genetic predisposition to osteoarthritis is characterized by a complex interaction of multiple genetic variants and epigenetic factors that influence the expression of key genes involved in cartilage health and disease progression. Understanding these mechanisms is vital for developing targeted therapeutic strategies for OA.

3.2 Molecular Pathways Involved in OA ​

Osteoarthritis (OA) is a complex and multifactorial degenerative joint disease characterized by the degradation of articular cartilage, synovial inflammation, and alterations in subchondral bone. The pathogenesis of OA involves a variety of genetic, molecular, and environmental factors that contribute to its development and progression.

Genetic studies have demonstrated that genetic variation plays a significant role in OA, with heritability estimates suggesting that approximately 50% of OA cases can be attributed to genetic factors. Specific genes associated with OA have been identified through genome-wide association studies (GWAS), including those involved in signaling pathways related to bone morphogenetic proteins (BMP), inflammatory responses, and apoptotic processes (Valdes and Spector 2010) [19]. Furthermore, genes such as GDF5 and COL6A4 have been implicated in the disease, highlighting the involvement of structural and inflammatory pathways in OA susceptibility (Valdes and Spector 2010) [19].

Molecular mechanisms underlying OA involve various signaling pathways that regulate cartilage homeostasis, inflammation, and cellular apoptosis. Key pathways implicated in OA include the mitogen-activated protein kinase (MAPK) signaling pathway, the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the Wnt signaling pathway. These pathways are critical for chondrocyte survival, extracellular matrix remodeling, and the inflammatory response (Hiruthyaswamy et al. 2025) [22].

In addition to genetic factors, epigenetic modifications, such as DNA methylation and histone modifications, have been shown to influence gene expression in OA. Studies indicate that altered DNA methylation patterns in chondrocytes can affect the expression of genes associated with cartilage integrity and inflammation, thereby contributing to OA pathophysiology (Gabay and Clouse 2016) [21]. For instance, genes like DLX5 and AXIN2 have been identified as significantly different in both DNA methylation and mRNA expression profiles between OA patients and healthy controls (He et al. 2018) [23].

Moreover, inflammatory cytokines, such as interleukins and tumor necrosis factor-alpha (TNF-α), play a crucial role in the pathogenesis of OA by promoting synovial inflammation and cartilage degradation. These cytokines activate signaling pathways that lead to the expression of matrix metalloproteinases (MMPs), which are responsible for extracellular matrix breakdown (Wang et al. 2011) [24].

Recent research has also highlighted the role of microRNAs (miRNAs) in OA, which are non-coding RNAs that regulate gene expression post-transcriptionally. Several miRNAs have been implicated in the modulation of signaling pathways associated with chondrocyte apoptosis, inflammation, and matrix degradation (Xu et al. 2016) [25].

In summary, the mechanisms of osteoarthritis are underpinned by a complex interplay of genetic predispositions, molecular signaling pathways, epigenetic modifications, and inflammatory processes. These insights into the molecular pathways involved in OA provide potential targets for therapeutic intervention, aiming to halt or reverse the progression of this debilitating disease.

4 Role of Mechanical Factors ​

4.1 Joint Loading and Biomechanics ​

Osteoarthritis (OA) is a multifaceted degenerative joint disease characterized by a complex interplay of mechanical and biochemical factors that contribute to its pathogenesis. The mechanisms of OA involve both the physical loading of joints and the resulting biological responses, highlighting the critical role of biomechanics in the disease's progression.

Mechanical loading is essential for maintaining healthy cartilage, as moderate mechanical stress is necessary for cartilage homeostasis. However, abnormal joint loading—often resulting from factors such as obesity, trauma, or malalignment—can increase the risk of developing OA. For instance, studies indicate that altered joint loading is a critical risk factor for joint degeneration, with obesity being particularly significant due to the increased mechanical stress it places on weight-bearing joints [26][27].

The initiation and progression of OA can be influenced by both the magnitude and duration of joint loading. Research has shown that dynamic activities can significantly impact the mechanical environment of the joint, which in turn affects the development of OA. The specific patterns of loading and the associated muscle activation play crucial roles in how OA progresses and how patients respond to treatments [28][29].

Moreover, the interaction between mechanical factors and inflammatory processes is pivotal in the context of OA. Inflammatory cytokines are often elevated in joints affected by OA, and these pro-inflammatory mediators can exacerbate cartilage degeneration. In vivo studies have demonstrated that mechanical stress can influence the production of these inflammatory mediators, further complicating the disease process [30][31]. For example, mechanical load has been shown to regulate matrix metabolism and cell viability, suggesting that chondrocytes respond to mechanical stimuli through various mechanotransduction pathways [32].

In the context of subchondral bone health, mechanical loading plays a dual role. Disrupted loading patterns can lead to pathological changes in the subchondral bone, which often serve as initiating factors for joint degeneration. Conversely, appropriate mechanical loading may help maintain bone health and slow the progression of OA [31]. The mechanisms through which mechanical load influences subchondral bone involve remodeling processes that can either promote or inhibit the development of OA [33].

In summary, the mechanisms of osteoarthritis are intricately linked to mechanical factors, where both abnormal loading and the resultant biological responses contribute to the disease's onset and progression. Understanding these interactions provides insights into potential therapeutic approaches, emphasizing the importance of managing mechanical factors to improve joint health and mitigate the effects of OA [34].

4.2 Impact of Physical Activity ​

Osteoarthritis (OA) is a complex and multifactorial disease characterized by the degeneration of articular cartilage and other joint tissues. Among the various mechanisms implicated in its pathogenesis, mechanical factors play a crucial role. These mechanical factors encompass both the stresses applied to the cartilage and the resultant biological responses, particularly in relation to physical activity.

Mechanical factors have long been recognized as significant contributors to the etiology of OA. The primary hypotheses surrounding cartilage damage suggest that excessive stress application and fatigue mechanisms are central to the process of mechanical failure. Cartilage, being a living tissue, has a failure threshold that is influenced by the mechanical stresses experienced in a joint. Prolonged periods of low-level activity, if followed by short bursts of intense activity, may expose weakened cartilage to damaging stresses, potentially leading to OA development [35].

Recent studies have highlighted the role of fluid shear forces as a key biomechanical stimulus in both the maintenance of cartilage health and the progression of OA. Fluid shear stress affects the physiological functions and signaling pathways of chondrocytes, which are essential for cartilage homeostasis. The interaction between mechanical loading and biochemical pathways is critical, as mechanical loading influences the metabolism of cartilage and its response to injury [33].

Furthermore, the biomechanical environment of a joint, which can be altered by factors such as trauma, joint instability, disuse, or obesity, significantly influences the initiation and progression of OA. Evidence from clinical and animal studies indicates that mechanical changes, including those induced by joint injuries, lead to increased concentrations of inflammatory cytokines in the joint, thereby exacerbating cartilage degeneration [30]. This interaction between biomechanical factors and inflammation is particularly evident in posttraumatic arthritis, where mechanical loading serves as a potent regulator of matrix metabolism and cell viability [30].

The relationship between physical activity and OA is nuanced. While regular, moderate physical activity is beneficial for joint health and can help maintain cartilage integrity, excessive or inappropriate loading can lead to injury and subsequent OA. Research suggests that both the rate of exerted loads and muscle activation patterns are critical in understanding OA etiology and treatment. Studies have shown that specific biomechanical factors, such as the knee adduction moment and muscle strength, are increasingly recognized as contributors to the pathogenesis of knee OA [36].

In summary, the mechanisms of osteoarthritis, particularly concerning mechanical factors, emphasize the importance of the biomechanical environment and physical activity levels. The balance between adequate mechanical loading for cartilage health and the risks associated with excessive or improper loading is pivotal in the prevention and management of OA. Future research should continue to explore these interactions to inform effective therapeutic strategies and interventions for OA.

5 Systemic Factors Influencing Osteoarthritis ​

5.1 Obesity and Metabolic Syndrome ​

Osteoarthritis (OA) is a complex and heterogeneous disorder influenced by various systemic factors, particularly obesity and metabolic syndrome. The pathogenic mechanisms underlying OA extend beyond mechanical stress, involving metabolic and inflammatory processes that significantly contribute to joint damage and disease progression.

Obesity is recognized as a major risk factor for OA, affecting both weight-bearing and non-weight-bearing joints. It contributes to OA through two primary mechanisms: mechanical overload and systemic inflammation. The mechanical aspect involves increased load on the joints due to excess body weight, which accelerates wear and tear on articular cartilage. However, the systemic effects of obesity are equally critical, as they lead to a chronic low-grade inflammatory state. This inflammation is largely driven by adipose tissue, which secretes pro-inflammatory cytokines and adipokines that can adversely affect joint tissues, promoting cartilage degradation and synovial inflammation (Courties et al., 2019; Sowers, 2001).

Metabolic syndrome-associated osteoarthritis (Met-OA) is a clinical phenotype characterized by the interplay between obesity, metabolic dysfunction, and chronic inflammation. The components of metabolic syndrome—such as hypertension, dyslipidemia, and type 2 diabetes—further exacerbate the risk of developing OA. For instance, the presence of insulin resistance and abnormal lipid metabolism can lead to increased levels of circulating inflammatory mediators, which contribute to joint inflammation and catabolism (Courties et al., 2017; Sellam & Berenbaum, 2013).

Research has shown that the adipose tissue in obese individuals produces various inflammatory mediators, including cytokines and free fatty acids, which can impair cartilage homeostasis and promote the catabolic processes in joint tissues. The elevation of these mediators correlates with increased severity of OA, highlighting the role of obesity-related inflammation in modulating disease progression (Wang et al., 2015; Jiménez-Muro et al., 2023).

Moreover, recent studies suggest that gut microbiota may also play a role in the development of obesity-related OA. Dysbiosis, or an imbalance in gut microbiota, has been linked to increased systemic inflammation and metabolic disturbances, which can further contribute to joint inflammation and degradation (Liu et al., 2019; Wei et al., 2023).

In summary, the mechanisms of osteoarthritis are multifaceted, with obesity and metabolic syndrome acting as significant systemic factors. These conditions promote chronic low-grade inflammation, disrupt metabolic homeostasis, and contribute to joint tissue degradation through a complex interplay of mechanical and biochemical processes. Effective management of OA should therefore consider these systemic factors, focusing on weight control, metabolic health, and inflammation reduction to improve patient outcomes (Shumnalieva et al., 2023; Batushansky et al., 2022).

5.2 Inflammatory Markers and Systemic Conditions ​

Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by complex interactions among various biological and environmental factors. The mechanisms underlying OA involve a combination of systemic factors, inflammatory markers, and their interplay with other conditions.

A significant aspect of OA pathogenesis is the concept of "inflammaging," which refers to a chronic, low-grade inflammatory state associated with aging. This condition is driven by endogenous signals and is characterized by the production of reactive oxygen species and inflammatory cytokines, contributing to cartilage degradation. Elevated systemic and local inflammatory cytokines, along with senescent molecules, promote the degeneration of cartilage, while the immune response, involving changes in B and T lymphocyte populations, further exacerbates joint damage through self-reactivity (Motta et al. 2023) [37].

The role of inflammatory mediators is crucial in the progression of OA. Pro-inflammatory cytokines, such as IL-1 and TNF-alpha, are involved in the degradation of the extracellular matrix (ECM) of cartilage, primarily through the activation of matrix metalloproteinases (MMPs). These enzymes, whose activity is not adequately counterbalanced by tissue inhibitors, lead to an imbalance favoring cartilage destruction over repair (Iannone & Lapadula 2003) [38]. Furthermore, synovial inflammation, characterized by an influx of inflammatory cells and mediators, plays a pivotal role in the degenerative process of OA, highlighting the importance of inflammation in the disease's etiology (Raman et al. 2018) [39].

In addition to local inflammatory responses, systemic factors such as obesity and metabolic disorders significantly influence OA development. Obesity is associated with increased mechanical stress on joints, but it also contributes to systemic inflammation, exacerbating the disease (Li et al. 2024) [34]. This interplay between mechanical and inflammatory factors underscores the complexity of OA as not merely a localized joint disease but as one influenced by systemic health conditions.

Moreover, the emerging understanding of epigenetic factors in OA suggests that environmental factors can induce changes in gene expression without altering DNA sequences. These epigenetic modifications may perpetuate the inflammatory responses and contribute to the chronic nature of OA (Fathollahi et al. 2019) [40].

Overall, the mechanisms of osteoarthritis are characterized by a dynamic interplay of local and systemic factors, with inflammation playing a central role in the disease's progression. The recognition of these mechanisms not only enhances the understanding of OA pathophysiology but also opens avenues for potential therapeutic interventions targeting both local joint health and systemic conditions that contribute to the disease.

6 Advances in Imaging and Biomarkers ​

6.1 Imaging Techniques for OA Assessment ​

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6.2 Potential Biomarkers for Early Detection ​

Osteoarthritis (OA) is a complex degenerative joint disease characterized by the progressive loss of articular cartilage, subchondral bone changes, and synovial inflammation, leading to joint pain and dysfunction. The mechanisms underlying OA are multifactorial, involving a combination of biological, mechanical, and environmental factors.

Recent studies have identified critical molecular mechanisms and signaling pathways that contribute to the progression of OA. For instance, bioinformatics analyses have highlighted the role of differentially expressed genes (DEGs) in OA, which are significantly involved in biological processes such as extracellular matrix (ECM) binding, immune receptor activity, and cytokine activity. Key signaling pathways identified include cytokine receptors, ECM-receptor interaction, and the PI3K-Akt pathway. Notably, in OA cartilage, signaling pathways such as AMPK, B cell receptor, IL-17, and PPAR are downregulated, while pathways like calcium signaling, cell adhesion molecules, TGF-β signaling, and Wnt signaling are upregulated, indicating their potential role in disease progression (Wang et al. 2024) [41].

The inflammatory nature of OA is also underscored by the involvement of inflammatory biomarkers in its pathogenesis. Recent research has emphasized the prognostic value of specific biomarkers, which could facilitate early identification and treatment of patients at risk for OA. These biomarkers include pro-inflammatory cytokines, microRNAs, and other molecular indicators that reflect the ongoing pathological processes within the joint (Braaten et al. 2022) [42].

In terms of imaging and diagnostic advancements, the application of biomarkers presents a promising avenue for the early detection of OA. Biomarkers derived from cartilage breakdown, inflammation, and metabolic changes in joint tissues can provide insights into disease severity and progression. For example, biochemical markers such as collagen degradation products and various inflammatory mediators have been utilized to monitor disease status and response to therapy (Patra & Sandell 2011) [43].

The integration of advanced imaging techniques with biomarker assessments could enhance the diagnostic capabilities for OA. Radiographic findings often lag behind biochemical changes, making the identification of biomarkers crucial for early intervention strategies. A combination of biomarkers from different biological fluids, such as serum, urine, and synovial fluid, could improve the accuracy of OA diagnostics and enable more personalized treatment approaches (Nguyen et al. 2017) [44].

In summary, the mechanisms of osteoarthritis involve a complex interplay of genetic, environmental, and mechanical factors leading to joint degradation. Advances in biomarker research and imaging technologies are pivotal for early detection and understanding the underlying pathophysiological processes, ultimately aiming to improve patient outcomes through timely and targeted interventions.

7 Conclusion ​

The mechanisms underlying osteoarthritis (OA) are multifaceted, encompassing cartilage degradation, subchondral bone changes, synovial inflammation, genetic predisposition, mechanical factors, and systemic influences such as obesity and metabolic syndrome. Key findings highlight the role of matrix metalloproteinases (MMPs) in cartilage degradation, the importance of subchondral bone remodeling in disease progression, and the significant contribution of synovial inflammation to joint dysfunction. Current research underscores the need for a holistic understanding of OA as a disease affecting the entire joint, rather than just the cartilage. Future studies should focus on elucidating the interactions between these various mechanisms and identifying novel therapeutic targets, particularly in the context of inflammatory pathways and metabolic factors. The integration of advanced imaging techniques and biomarker research holds promise for enhancing early detection and monitoring of OA, ultimately improving patient management and outcomes.

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