Osteoarthritis (OA) is a chronic degenerative joint disorder and major contributor to disability, which is typified by persistent pain and entire arthropathies such as synovitis, articular cartilage loss, subchondral bone remodeling, and osteophyte formation (Tong et al., 2022). It is a prevalent condition that affects millions of people over 65 years of age worldwide (Ansari et al., 2024). In recent years, growing attention has been paid to the critical role of metabolic disturbances, particularly obesity, in the onset and progression of OA. Obesity is recognized as a major preventable risk factor for the development of OA. Numerous studies have shown a strong link between body mass index (BMI) and OA in various joints (Zheng and Chen, 2015; Zhou et al., 2014), including the hip (Liu et al., 2022; Rosa et al., 2021), knee (Liu et al., 2022; Niu et al., 2017; Zheng and Chen, 2015), foot, and hand. However, the precise mechanism by which obesity contributes to disease onset and progression remains unclear. The well-documented association between BMI, altered limb alignment, knee OA, and the positive effects of weight loss supports the conventional idea that obesity affects joints by increasing biomechanical pressure and altering movement patterns. Obesity is now understood to be a low-grade systemic inflammatory condition (Khanna et al., 2022). This suggests that metabolic factors linked to obesity may increase the levels of proinflammatory cytokines, which are also associated with OA. Consequently, the impact of obesity on OA likely results from a complex interaction between genetic, metabolic, and biomechanical factors (Conde et al., 2011b; Griffin and Guilak, 2008; Plebańczyk et al., 2019; Yuan et al., 2021).

The pathophysiology of OA is increasingly being understood to be influenced by metabolic factors, where obesity-driven inflammation and metabolic syndrome accelerate joint degeneration (De Roover et al., 2023; Yunus et al., 2020). Adipose tissue, in addition to serving as an energy reservoir (Choe et al., 2016), is an active endocrine organ that secretes bioactive substances known as adipocytokines or adipokines (Coelho et al., 2013), which have been linked to the inflammatory and degenerative processes of OA (Xie and Chen, 2019). The interplay between mechanical stress and obesity-mediated biochemical factors, including oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, creates a complex pathological environment that drives OA progression (Azamar-Llamas et al., 2017; Hülser et al., 2021; King et al., 2013). Adipokines secreted by adipose tissue play a crucial role in maintaining the metabolic balance of cartilage by regulating the secretion of cytokines, chemokines, matrix-degrading enzymes, and cell growth and differentiation factors (Conde et al., 2011b; Xie and Chen, 2019). In OA pathogenesis, adipocytes release both adipokines and proinflammatory cytokines. These adipokines stimulate chondrocytes to express a range of proinflammatory mediators and matrix-degrading enzymes such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinases (MMPs) (González-Rodríguez et al., 2022; Mukherjee and Das, 2024; Wang and He, 2018). It can accelerate the breakdown of cartilage's extracellular matrix (ECM), further contributing to joint degeneration. In addition to promoting inflammation and ECM degradation, the presence of adipokines in the joint environment is associated with mitochondrial dysfunction, which often precedes visible cartilage breakdown. Mitochondrial dysfunction, a hallmark of metabolic stress (Prasun, 2020), arises from the increased production of reactive oxygen species (ROS) in response to proinflammatory signals. Oxidative stress damages mitochondrial DNA (Kowalczyk et al., 2021) and impairs mitochondrial respiration, contributing to cellular damage and death (Kowalczyk et al., 2021). As a result, chondrocytes become less capable of maintaining cartilage integrity, leading to apoptosis and exacerbating cartilage degradation (de Mello et al., 2018; Rossmann et al., 2021).

Studies have observed low-grade chronic inflammation specific to obesity-induced OA, distinguishing it from other OA phenotypes (Sun et al., 2021). In obesity-associated OA, adipose tissue produces an array of adipokine factors, including leptin and adiponectin, along with cytokines such as IL-1 and TNF-α, which promote the deterioration of chondrocytes and ECM breakdown in joints like the knee (Francisco et al., 2018a; Giardullo et al., 2021; Xie and Chen, 2019). It has been suggested that adipokines, particularly leptin and adiponectin, released from the synovium, infrapatellar fat pad (IPFP), and osteophyte cells can upregulate inflammatory mediators such as prostaglandin E2 (PGE2), IL-6, IL-8, TNF-α, and vascular cell adhesion molecule 1 (VCAM-1) in knee synovial fluid (SF) (Francisco et al., 2019b). These secretory proteins enhance cartilage infiltration, triggering a degenerative cascade that further accelerates OA progression. Similarly, it was found that adipokine levels were significantly higher in patients with OA, and after adjusting for variables such as age, sex, and BMI, these elevated adipokine levels remained associated with OA severity (Bas et al., 2014; de Boer et al., 2012). When adipokines induce mitochondrial dysfunction (Woo et al., 2019), they further exacerbate ER stress (Chu et al., 2019; Malhotra and Kaufman, 2011), which increases oxidative stress and creates a feedback loop that perpetuates inflammation and cartilage destruction.

Adipokines interact with ER stress mechanisms by influencing protein folding pathways and disrupting cellular functions (Chen et al., 2023; Kim et al., 2023). For example, leptin, an adipokine that is typically elevated in obesity, has been shown to modulate ER stress signaling (Hosoi et al., 2008; Ramírez and Claret, 2015), leading to the production of proinflammatory cytokines (Loffreda et al., 1998; Otero et al., 2006). These cytokines further aggravate joint inflammation and degradation by triggering processes that harm chondrocytes and contribute to cartilage breakdown. Increased ER stress in joint cells due to adipokine signaling creates a vicious cycle: adipokines stimulate inflammatory pathways, leading to increased production of misfolded proteins within the ER, which further amplifies cellular stress. As ER stress progresses, the unfolded protein response (UPR) fails to restore protein homeostasis and apoptotic pathways are activated (Hetz, 2012; Oslowski and Urano, 2011). This cellular damage contributes to the loss of cartilage integrity and worsening of OA. Additionally, ER stress also affects other joint components like the synovium and bone tissue. Adipokines promote the activation of fibroblast-like synoviocytes and osteoclasts, leading to increased synovial inflammation and subchondral bone remodeling both of which are significant in OA pathogenesis (Wen et al., 2023). This connection between adipokines and ER stress underscores the intricate relationship between metabolic disturbances in obesity and joint degeneration (Lee et al., 2022; Schwarz and Blower, 2016; Wen et al., 2023).

In this review article, we aim for a comprehensive discussion of the complex mechanisms that contribute to the relationship between adipocytokine signaling pathways and OA pathogenesis, with a specific focus on the role of obesity-mediated metabolic disruptions. While OA has traditionally been understood as a mechanical wear-and-tear disease affecting weight-bearing joints, emerging evidence highlights the significant contribution of metabolic factors, particularly obesity-related inflammation, in accelerating disease onset and progression. This review further explores how obesity-induced mitochondrial dysfunction, oxidative stress, and ER stress interact with adipokine signaling, creating a pathological environment that exacerbates joint degradation. A detailed analysis of the signaling pathways regulated by pathogenic adipokines will be provided to better understand their roles in OA progression. By identifying key pathways and molecular targets involved in adipokine-driven OA pathogenesis, this review seeks to pave the way for novel therapeutic strategies to mitigate OA progression through the modulation of adipokine signaling and metabolic dysfunctions. In doing so, it opens avenues for developing more effective treatments that can halt or reverse the degenerative effects of obesity-driven OA.