Abstract
Purpose of Review
Metabolic syndrome (MetS), also called the ‘deadly quartet’ comprising obesity, diabetes, dyslipidemia, and hypertension, has been ascertained to have a causal role in the pathogenesis of osteoarthritis (OA). This review is aimed at discussing the current knowledge on the contribution of metabolic syndrome and its various components to OA pathogenesis and progression.
Recent Findings
Lately, an increased association identified between the various components of metabolic syndrome (obesity, diabetes, dyslipidemia, and hypertension) with OA has led to the identification of the ‘metabolic phenotype’ of OA. These metabolic perturbations alongside low-grade systemic inflammation have been identified to inflict detrimental effects upon multiple tissues of the joint including cartilage, bone, and synovium leading to complete joint failure in OA. Recent epidemiological and clinical findings affirm that adipokines significantly contribute to inflammation, tissue degradation, and OA pathogenesis mediated through multiple signaling pathways. OA is no longer perceived as just a ‘wear and tear’ disease and the involvement of the metabolic components in OA pathogenesis adds up to the complexity of the disease.
Summary
Given the global surge in obesity and its allied metabolic perturbations, this review aims to throw light on the current knowledge on the pathophysiology of MetS-associated OA and the need to address MetS in the context of metabolic OA management. Better regulation of the constituent factors of MetS could be profitable in preventing MetS-associated OA. The identification of key roles for several metabolic regulators in OA pathogenesis has also opened up newer avenues in the recognition and development of novel therapeutic agents.
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Introduction
Osteoarthritis (OA) is the most common type of arthritis affecting about 3.3 to 3.6% of the world’s population. It is the 11th most debilitating disease across the globe inflicting moderate to severe disability in about 43 million people [1]. According to the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD) report, OA ranked among the highly prevalent rheumatic musculoskeletal disorder that had affected around 303 million people worldwide in 2017 with an overwhelming estimate of 9,604,000 years lost to OA-associated disability [2]. In the USA, it is estimated that 80% of the population above 65 years of age exhibit radiographic evidence of OA. Not to mention the intense physical and emotional ramifications manifested with the disease, OA is also affiliated with a huge personal, societal, and economic burden. OA was the second most expensive medical condition treated in US hospitals in 2013, contributing for 4.3% ($18.4 billion) of the $415 billion total cost of hospitalization [3]. OA patients are at a greater risk of all-cause mortality especially for cardiovascular diseases bearing direct relevance to the level of disability [4]. The enormous disease encumbrance associated with OA led to the submission of a White Paper by Osteoarthritis Research Society International (OARSI) in 2016, describing OA as a serious disease [5].
More than being just a disease of the articular cartilage, OA has been identified as a complex multi-factorial degenerative disease involving various components of the entire joint [6]. Advancing deterioration and destruction of articular cartilage accompanied by diverse structural and functional alterations in various tissues of the joint including subchondral bone remodeling, osteophyte formation, development of bone marrow lesions, synovial inflammation, weakening of the periarticular muscles, and modifications in the joint capsule, ligaments, and menisci have all been identified to be the hallmarks of OA [7,8,9,10]. OA may develop in any joint, but the knees, hips, hands, facet joints, and feet are the most commonly affected, with women having a higher prevalence rate compared to men [11]. It has been estimated that the global prevalence of knee OA was 16% in individuals aged 15 and over and 22.9% in individuals aged 40 and over [12•]. Various factors have been implicated to have a role in the disease pathogenesis of OA constituting discrete phenotypes including post-traumatic, ageing-related, genetic, and symptomatic [13], eventually resulting in clinical and radiographic manifestations. While it was originally thought that OA was a disease of the elderly, risk factors other than age have been identified to predispose an individual to OA. The prevalence of OA is on the rise and is attributed partly to a surge in the preponderance of OA risk factors, including obesity, lack of physical activity, and traumatic injuries of the joint. Compelling evidence from recent studies connote that OA could be a metabolic disease with several components of the metabolic syndrome (MetS) adding up to the disease pathogenesis and progression and that metabolic syndrome increased the risk for OA [14,15,16]. Metabolic syndrome, also called the syndrome X, is a clustering of closely associated clinical conditions comprising central obesity, glucose intolerance (type 2 diabetes, impaired glucose tolerance), insulin resistance (IR), dyslipidemia, and hypertension, all of which present a risk for cardiovascular diseases [17]. Of late, there has been a profound interest to decipher the plausible link between these metabolic perturbations and OA that has led to the identification of yet another phenotype of OA known as the metabolic OA [18, 19]. Evidence(s) from cohort studies have ascertained a strong positive association between metabolic syndrome and OA incidence and that there was a significant increase in the risk for developing OA with the addition of each component of metabolic syndrome [20]. This review is focused on discussing the contribution of each of the several components of the metabolic syndrome towards OA pathogenesis and progression.
Obesity and OA
Osteoarthritis (OA) is a complex disease having a multifactorial pathophysiology comprising biomechanical, metabolic, and inflammatory components to its etiology [21]. Obesity has been long established as a predominant and possibly avertable risk factor for OA, possessing multiple repercussions on the incidence, progression, and symptom severity associated with the disease. The role of obesity and overweight in contributing to OA progression is conceivably the most commonly researched topic in OA research. Several epidemiological studies have established the link between obesity and OA as listed in Table 1. A positive association between higher body mass and greater lower extremity joint loading has been established [22]. Coggon et al. [23] reported that subjects whose body mass index (BMI) exceeded 30 kg/m2 had 6.8 times greater risk of developing knee OA compared to subjects who recorded normal body weights. Excess body weight not only enhances the load on the weight-bearing joints [24] but also causes misalignment and unfavorable joint mechanics especially in the knees thereby increasing mechanical stress and cartilage degradation leading to OA [25]. Also, obesity is associated with a reduction in muscle strength highly essential for joint stabilization and hence consequently a decrease in the ability to withstand mechanical stress in the joints [26]. In addition to its direct detrimental effects on the cartilage matrix, mechanical loading can also alter the inflammatory state of chondrocytes. Application of high-magnitude cyclic tensile strain to chondrocytes significantly elevated the expression of pro-inflammatory mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and matrix metalloproteinases (MMPs)-3, -13 mediated through FAK, ERK, JNK, p38, and NF-κB signaling [27,28,29]. Mechanical overloading has also been identified to promote chondrocyte senescence and OA development in human and mice chondrocytes [30]. Evidence(s) from in vivo studies indicate that compressive loading of the knee joints led to increased cartilage fibrillation and erosion, and osteophyte formation [31]. In addition to cartilage, obesity could also adversely affect the subchondral bone where the mechanical overburdening leads to thickening of subchondral cortical bone impairing the underlying cartilage [32, 33], and induce an inflammatory phenotype in both sclerotic and non-sclerotic osteoblasts identified by an increase in their expression of IL-6, IL-8, COX-2, Receptor activator of nuclear factor kappa-Β ligand (RANKL), MMP-3, MMP-9, and MMP-13 with a decrease in osteoprotegerin (OPG) expression resulting in an increased susceptibility to OA [34]. In obese subjects, malalignment and hyperextension in the knee joints also contributes to OA [35].
Although excessive joint loading contributes for an important etiological factor for obesity-mediated OA, altered biomechanics fully fail to justify the increased risk for OA in non-weight-bearing joints including the hands and the wrists in obese subjects, pointing to a systemic, non-mechanical influence on the risk for OA [36]. Indeed, perpetual inflammation leading to cartilage loss, osteophyte formation, and synovitis have been implicated as the main pathophysiological mechanism behind obesity-associated OA [37]. The adipose tissue (AT) is a complex and a highly metabolic organ comprising adipocytes, nerve tissue, stromovascular cells, and immune cells such as the macrophages, T cells, B cells and dendritic cell subsets, mast cells, neutrophils, and eosinophils [38]. Under obese conditions, the adipose tissue macrophages (ATMs) infiltrating and accumulating in the adipose tissue with increasing body weight undergo a phenotype switch leading to a shift in their activation state from an M2-polarized state (lean) that protect adipocytes from inflammation to an M1 pro-inflammatory state that leads to enhanced production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12, IL-15, IL-17, IL-18, IL-23), chemokines (monocyte chemoattractant protein (MCP)-1, C-X-C motif ligand (CXCL)-9, CXCL-10, CXCL-11, CXCL-13, C–C motif ligand (CCL)-8, CCL-15, CCL-19, CCL-20), interferon (IFN)-γ, and reactive oxygen species (ROS) such as nitric oxide (NO) resulting in chronic low-grade sterile inflammation and IR [39,40,41,42]. The role of IR in the pathophysiology of OA has been discussed elsewhere in this manuscript.
Higher levels of pro-inflammatory cytokines have been observed in overweight and obese adults [43]. Evidences from experimentally induced obesity in rats using a high-carbohydrate/high-fat diet also revealed a spontaneously induced infiltration of pro-inflammatory macrophages (M1) into the synovium of the joint tissue and also an activation of the M1 phenotype in the resident macrophages with a concomitant exacerbation of OA-like pathological changes [44]. The M1-associated cytokines IL-6, IL-1β, and TNF-α promote detrimental processes in chondrocytes such as decreased production of collagen II and aggrecan, and upregulation of several inflammatory molecules and matrix-degrading proteases mediated by the various signaling pathways including the transforming growth factor (TGF)-β, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, AKT, NF-κB, and β-catenin signaling that result in cartilage degradation and bone resorption [45]. IL-1β plays a potential catabolic role in OA where it stimulates chondrocytes to release increased amounts of A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS)-4, ADAMTS-5, MMP-1, MMP-3, MMP-13, and other intermediates including ROS, NO, cytosolic phospholipase A2 (cPLA2), COX-2, and prostaglandin E2 (PGE2) and also regulate Fas-mediated chondrocyte apoptosis. IL-1β also exerts a detrimental effect on osteoblasts by increasing the expression of MMP-2, MMP-3, MMP-9, MMP-13, ADAMTS-4, ADAMTS-5, and RANKL contributing to subchondral bone remodeling OA [37, 46]. TNF-α plays a critical role in OA by its ability to induce collagenases and aggrecanases including MMP-1, MMP-3, MMP-13, ADAMTS-4, IL-6, IL-8, RANTES, VEGF, iNOS, COX-2, and PGE2 synthase while also inhibiting the synthesis of proteoglycan components and collagen II [47]. TNF-α and IL-1β have also been demonstrated to significantly decrease the expression of SOX9, which is essential for chondrocyte differentiation [48, 49]. IL-6 has been identified to induce catabolic mediators in MMP-3, MMP-13, and ADAMTS which mediate cartilage degeneration, promote proteoglycan loss, reduce chondrocyte proliferation, and enhance ROS production. IL-6 has also been identified to affect other tissues of the joint including synovium, subchondral bone, and muscles in the context of OA [50]. IL-1 and IL-6 have also been identified to play decisive roles in driving Th17 signaling leading to the production of IL-17 [51, 52]. IL-17 could regulate several OA pathophysiology-related pathways in chondrocytes and synovial fibroblasts (SFs) observed in end-stage OA patients [53•]. In addition to solely effecting adverse effects on the cartilage structure and function, the pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, IL-15, IL-17, and IL-18 could also work in synergy with one another to maximize their potent adverse effects in OA including enhancing inflammation and upregulating the expression of proteases, aid cartilage ECM degradation, and ultimately resulting in total joint failure [37, 42].
Furthermore, the factors secreted by M1 synovial macrophages have been demonstrated to impede the chondrogenic differentiation of the resident mesenchymal stem cells in the OA synovium suggestive of the fact that the M1-polarized macrophage subsets orchestrate an anti-chondrogenic effect within the OA joint [54]. Recently, Liu et al. [55] reported a markedly higher ratio of M1 to M2 macrophages in the synovial fluid (SF) and peripheral blood of knee OA patients compared to controls with a significant positive correlation with the level of Kellgren–Lawrence grade in knee OA, strongly suggestive of the involvement of macrophages in knee OA pathogenesis. The shift in macrophage phenotype from M2 to M1 with increasing adiposity significantly augments the M1 cytokine-induced cartilage deterioration and diminishes the efficacy for tissue repair and angiogenesis mediated by the M2 macrophage-derived factors. Therefore, prospective therapeutic approaches directed at the synovial macrophage phenotype could be decisive in breaking the bond between obesity and OA and also promote the efficiency of MSC-based cartilage regeneration approaches [56, 57].
In obesity, the adipose tissue (AT) has been recognized to function as the largest endocrine metabolic organ secreting a battery of pro-inflammatory cytokines, chemokines, and adipokines. Adipokines comprise a range of pleiotrophic molecules including bioactive peptides and immune and inflammatory mediators secreted by the adipose tissue, and exhibit their effects in an autocrine/paracrine and endocrine manner [58]. The infrapatellar fat pad (IPFP) which is in close proximity with the synovium is the major source of adipokines in the SF of the knee. Despite the fact the adipokines are majorly secreted by adipocytes, other joint tissue resident cells including chondrocytes, osteoblasts, synoviocytes, stromal cells, macrophages, and immune cells have also been identified to produce some adipokines [59]. The presence of adipokine receptors in many joint cell types is indicative of the complex regulatory network of adipokine signaling within the joint.
Leptin was the first identified adipokine that is predominantly produced by the adipose tissue and executes its functions mediated by the Ob receptor [60]. Owing to the wide expression of leptin receptors in peripheral tissues and the involvement of leptin in several physiological processes including insulin secretion, bone metabolism, and immune responses, it is contemplated to be a potential link between obesity and OA. Higher levels of systemic leptin have been identified in OA patients in comparison to healthy subjects. Several studies have identified that significantly elevated leptin levels in OA patients were positively correlated with disease severity and pain [61,62,63,64], making it a potential biomarker for OA. One of the earlier studies showed that leptin could have an anabolic role on chondrocytes by inducing insulin-like growth factor 1 (IGF-1) and TGF-β expression [65]. However, in advanced OA cartilage and SF, the leptin and leptin’s receptor (Ob-Rb) are expressed in significantly increased levels. Leptin exerts a pro-inflammatory and catabolic function in cartilage metabolism by its inherent ability to function alone or in association with other pro-inflammatory factors to target chondrocytes, synoviocytes, and osteoblasts in exerting crucial functions of OA pathogenesis [66]. Inflammatory and catabolic factors such as IL-1β, MMP-9, and MMP-13 can induce the expression of leptin and in turn increase the production of T helper 1 (TH1) type cytokines by immune cells, and suppress TH2 type cytokines which corroborate a catabolic and pro-inflammatory role for leptin in OA pathophysiology [67, 68]. Adiposity in the absence of leptin signaling was found to be inadequate in inducing systemic inflammation and knee OA which underscores leptin’s noteworthy role in OA pathogenesis as well as its utility as a potential biomarker in OA [69].
The adipokine adiponectin, also known as AdipoQ, exerts its effects mediated through AdipoR1 and AdipoR2 receptors. While evidences from clinical and experimental studies point to a role for adiponectin in OA pathophysiology, it is yet not clear whether adiponectin exerts a protective role in OA or not. Adiponectin has been found to be expressed by synoviocytes, IPFP, osteophytes, cartilage, and bone tissues of the joint [70]. Two recent meta-analyses indicated that circulating adiponectin levels were elevated in OA patients compared to healthy controls [71, 72] whereas earlier studies showed decreased circulating levels of adiponectin in OA patients [73]. However, a positive association has been reported between increased serum adiponectin levels with a higher radiographic score in knee OA but not in hand OA suggestive of different pathological mechanisms in OA development of the two joints [74]. It has also been elucidated that adiponectin is upregulated in OA cartilage and the full-length form of adiponectin, but not the globular form, has a stimulatory effect on PGE2 and MMP-13 activity. It was also identified that AdipoR1 mRNA levels are strongly associated with the mRNA expression of cartilage-specific components, suggesting that adiponectin could be involved in matrix remodeling [75]. Recently, it was shown that there was a negative association between serum levels of adiponectin and bone mineral density (BMD) in symptomatic knee OA patients suggestive of its adverse effect on BMD [76]. Also, a recent cross-sectional study indicated that there was a greater association for synovial adiponectin with clinical severity of knee OA in women than for synovial leptin underscoring its clinical relevance in OA pathogenesis [77].
Visfatin, also known as the pre-B cell colony-enhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (NAMPT), is another key adipokine widely expressed in white adipose tissue (WAT) and implicated in OA [78, 79]. Studies have revealed that both circulating as well as SF visfatin levels were significantly higher in OA patients compared to healthy controls with the cartilage and synovial tissues of OA patients shown to exhibit higher secretion of visfatin compared to healthy subjects [80]. Besides, the IPFP tissue expression of visfatin in OA patients was found to be higher than that in matched subcutaneous WAT [81]. OA patients with greater radiographic evidence of joint damage and disease severity reportedly had higher levels of SF visfatin compared to those with less disease severity [82]. Visfatin has been found to be expressed in osteophytes by the osteoblasts, osteoclasts, and chondrocytes in OA patients indicating its destructive role in OA especially by unfavorably altering the extracellular matrix homeostasis resulting in cartilage destruction [83]. Visfatin has also been demonstrated to contribute to OA progression by its ability to exert a pro-inflammatory effect by inducing the production of IL-1β, IL-6, and TNF-α in lymphocytes [84].
The adipokine resistin is a cysteine-rich polypeptide hormone predominantly secreted by macrophages and adipocytes in humans and mice, respectively [85]. Resistin has been identified to have an association with radiographic knee OA [86]. Epidemiological and clinical studies have indicated that serum and SF resistin levels positively correlated with OA severity, synovitis, and structural abnormalities in OA patients [87,88,89]. With a role identified for resistin in enhancing the pro-inflammatory milieu by aiding the synthesis of MMPs and release of pro-inflammatory cytokines in chondrocytes, resistin is believed to promote OA progression [85]. Chemerin is another adipokine mainly expressed in the WAT, which exerts its functions by binding the ChemR23 receptor. Chemerin is a chemoattractant adipokine which stimulates chemotaxis of immune cells to the inflammatory site as in the case of OA where macrophages and other immune cells are recruited to the synovium as a part of the inflammatory cascade [90]. Obese patients have been reported to have increased levels of serum chemerin which is correlated to OA disease severity. The SF chemerin levels have been found to be positively correlated with BMI and OA severity [91]. With an inherent ability for the human articular chondrocytes to produce chemerin, express ChemR23, and also to promote inflammatory signaling [92], it is speculated that chemerin could play a role in OA pathogenesis.
Lipocalin -2 is another adipokine whose production within the joint tissues is triggered by both mechanical as well as inflammatory stimuli [93], serving as a sensor of mechanical load and joint inflammation in OA pathophysiology. Lipocalin-2 levels were found to be elevated in the synovial fluid and cartilage of OA patients, and proposed to be involved in matrix degradation by its ability to reduce chondrocyte proliferation and form a covalent complex with MMP-9 thereby preventing its auto-degradation [94]. Nesfatin-1 (nesfatin) is an N-terminal 82 amino acid peptide nucleobindin-2-derived adipokine implicated to have a role in OA. Serum nesfatin levels have been elevated in OA incidences [95], with the serum and SF concentrations found to be associated with radiographic severity in OA [96]. Moreover, the increased serum and chondrocyte expression levels of nesfatin-1 in OA subjects were found to be positively correlated with high-sensitivity C-reactive protein (hsCRP) and IL-18 levels [97], making it a prospective biomarker for OA progression. However, a recent study has reported that nesfatin-1 could protect against IL-1β induced OA progression in rats [98].
Apelin is another member of the adipokine superfamily highlighted to be associated with increased bone marrow lesions in OA [64]. A positive correlation was observed between SF apelin levels and disease severity in OA subjects with significantly elevated apelin levels identified in OA serum compared to the normal subjects. The expression of apelin and its receptor APJ was also relatively higher in OA cartilage compared to healthy controls suggestive of its role in contributing to OA pathophysiology [99]. Reports have identified a catabolic role for apelin in OA by virtue of its ability to induce the expression of inflammatory and matrix degrading proteases in vivo and in vitro [100, 101]. Apelin has also been reportedly identified to mediate the synovial VEGF-mediated angiogenesis in OA progression, making it an ideal pharmaceutical and therapeutic target in OA [102].
Owing to advancements in clinical research and the pursuit to gain newer knowledge concerning adipokine contribution to OA pathophysiology, novel adipokines are being identified lately. The novel adipokines such as Serpin Peptidase Inhibitor, Clade E, Member 2 (SERPINE2), WNT1 Inducible Signaling Pathway Protein 2 (WISP2), Glycoprotein Nmb (GPNMB), and Inter-Alpha-Trypsin Inhibitor Heavy Chain family, member 5 (ITIH5) are upregulated in obesity and have been identified to be expressed in the OA synovium, IPFP, and chondrocytes exhibiting differential expression patterns with a potential for involvement in OA onset and progression [103]. Another adipokine serum amyloid A (SAA) has been found to be significantly elevated in circulation as well as SF of OA patients and proven to contribute to the inflammatory process in OA [104]. Metrnl is another newly identified adipokine which has been discussed to have a connection with obesity–OA interplay [105]. The Retinol binding protein 4 (RBP4) is another novel adipokine that is a member of the lipocalin family that is produced within the OA joints and positively correlated with increased levels of adipokines and MMPs [106]. The fatty acid-binding protein 4 (FABP4) is a novel adipokine that is found in elevated levels in the circulation as well as the SF of OA patients with a positive correlation between the IPFP and SF levels, and perceived to be a potential biomarker for OA [107]. Adipsin is an adipokine recently identified to bear clinical relevance as a biomarker as well as potential therapeutic target for OA. Adipsin levels were significantly higher in human OA serum, SF, synovial membrane, and cartilage compared with controls. Higher serum adipsin levels have been reported in OA patients which was strongly associated with greater cartilage loss [108]. Also, adipsin deficiency in transgenic mice rendered protection against cartilage degradation when subjected to anterior cruciate ligament (ACL) injury thereby accentuating its role in OA [109]. In addition, a few adipokines such as omentin-1, vaspin, progranulin, and SERPINE2 have also been ascertained to play a protective role in OA progression [110,111,112,113]. The various roles of different adipokines in the context of OA have been discussed in Table 2.
OA and Dyslipidemia
Obesity is characterized not only by an abnormal loading of the weight-bearing joints, but also by an aberrant lipid metabolism leading to dyslipidemia identified by low levels of systemic high-density lipoproteins (HDLs) and higher levels of free fatty acids (FFAs), triglycerides (TGs), oxidized low-density lipoproteins (ox-LDLs), and cholesterol [114].
Altered lipid metabolism could well play a causal role in the pathobiology of OA as identified by several study findings. Epidemiological studies have also reported a positive correlation between hypercholesterolemia and OA [115], implying that cholesterol might be a systemic risk factor for OA. Studies carried out in rodents using ApoE−/− mice and diet-induced hypercholesterolemia (DIHC) rats showed that hypercholesterolemia was able to induce OA-like changes in these animals characterized by cartilage degradation, osteophyte formation, and alterations to the subchondral bone tissue architecture, accentuating the role of cholesterol in the pathogenesis of OA [116]. Impairment of cholesterol efflux genes accompanied by an increase in intracellular lipid accumulation in osteoarthritic chondrocytes has been established with a positive correlation to disease severity [117]. The downstream adverse effect of cholesterol accumulation in chondrocytes is manifested as an impairment of mitochondrial functions which could further exacerbate other downstream pathways critically involved in cartilage degradation such as ROS production, amplification of cytokine-induced chondrocyte inflammation, matrix catabolism, and increased chondrocyte apoptosis [118, 119]. Also, a recent study discovered that retinoic acid-related orphan receptor alpha in chondrocytes is directly activated by cholesterol and its metabolites, upregulating matrix-degrading enzymes and raising the risk of OA [120]. High levels of cholesterol also inhibited LRP3 gene in chondrocytes adversely affecting cartilage ECM metabolism and eventually resulting in OA cartilage degeneration [121]. Higher circulating levels of cholesterol and TG levels, and dysfunctional HDL have also been identified to accelerate joint pathology and induce cartilage loss in knee OA by synovial activation, ectopic bone formation [122], and an increased occurrence of bone marrow lesions which are a source of intense pain in OA [123].
In addition, reduced serum levels of HDL-c observed in the serum of OA patients could possibly have a propensity in OA pathogenesis. Studies using LCAT−/− and ApoA-1−/− (both are necessary to form mature HDL-c particles) mice have proven that these KO mice had greatly reduced levels of functional HDL-c and also exhibited cartilage fibrillation, vertical clefts, chondrocyte clustering, and reduced PG content with increased MMP-2, MMP-9, and MMP-13 expression compared to their controls [124]. Alterations in HDL-c metabolic pathway could adversely tinker cartilage homeostasis in an untoward direction leading to OA.
Higher circulating levels of ox-LDL are another feature of obesity-related dyslipidemia. In OA, inflammation accelerates vascular porosity expediting infusion of biological factors into the synovial fluid [125] including ox-LDL which has been oxidatively altered extra-articularly. In addition, activated endothelial cells in the inflamed synovium and chondrocytes in the degrading cartilage release ROS which could further oxidatively modify the native LDL to ox-LDL [126]. Binding of ox-LDL to its scavenger receptor—lectin-like ox-LDL receptor-1 (LOX-1)—reduces cell viability and PG synthesis in cartilage matrix, and increases intracellular ROS production leading to activation of NF-κB [127]. This further activates expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (IL-8, macrophage inflammatory protein-1b), enzymes (COX-2, iNOS, cPLA2, metalloproteinases), and adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) [128]. Also, ox-LDL/LOX-1 stimulates VEGF release in chondrocytes which increases the expression of proteinases like MMP-1, MMP-3, and MMP-13 and pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 leading to cartilage degradation [129]. Besides, chondrocytes in OA cartilage exhibit increased LOX-1 expression and localization in comparison to normal controls [130]. Chondrocytes express membrane receptors both for FAs and lipoproteins, including G-protein-coupled receptor 40 (GPR40) and GPR120, TLR4, and CD36, as well as some members of the low-density lipoprotein receptor (LDLR) and LDL receptor‐related protein (LRP) families [131]. The LRP5-mediated Wnt/β-catenin signaling pathway is involved in downregulating type II collagen production, while upregulating MMP-3 and MMP-13 synthesis thereby inducing cartilage degradation [132]. Ox-LDL could also trigger the release of MMPs, pro-inflammatory cytokines, and other growth factors by their inherent ability to also activate synovial macrophages, endothelial cells, and synovial fibroblasts [133]. These findings underline the significance of hypercholesterolemia and ox-LDL in the initiation and progression of OA by their inherent ability to impair the joint tissue homeostasis and induce inflammation and cartilage degradation.
Higher systemic FFA levels are also a characteristic of obesity-related dyslipidemia. Impairment in the inhibition of lipolysis in adipocytes is chiefly responsible for enhanced FFA release from adipose tissue into the circulation [134]. These FFAs induce a macrophage inflammatory response by triggering toll-like receptors (TLRs) and activating downstream signaling by phosphorylating TAK1, JNK, p-38, c-Jun, and NF-κB leading to the production of cytokines, iNOS, and COX-2 [135]. Resident macrophages of the synovial tissue lining can also be activated by FFAs to induce local joint inflammation. In addition, FFAs coming from a diet with imbalanced fat composition have also been shown to affect the various cells of the joint leading to inflammation and OA. Saturated fatty acids (SFAs) such as palmitic and stearic acid have been shown to promote chondrocyte matrix remodeling by activating autophagy [136]. Dietary saturated fatty acid palmitate promoted chondrocyte apoptosis and cartilage lesions in knee joint of mice mediated through the promotion of unfolding protein response (UPR)/endoplasmic reticulum (ER) stress in a mouse model of diet-induced OA [137]. In addition to chondrocytes, FAs and their derivatives function as signaling molecules to bind to receptors on the other joint tissue cells including osteoblasts, osteoclasts, and synoviocytes [131]. They activate various downstream signaling pathways to trigger detrimental effects on the joint including apoptosis of cells, altered tissue homeostasis, remodeling, and inflammation.
Diabetes and OA
Evidence from epidemiological and experimental data not only suggest a conceivable association between OA and diabetes but also endorse the proposition that diabetes could be in itself an important independent risk factor for OA [138]. OA and type 2 diabetes mellitus (T2DM) intermittently co-exist due to the common risk factors they share—obesity and aging and also due to their higher prevalence. Epidemiological studies reveal that the overall risk of OA in patients with T2DM is 1.46 while that of T2DM in patients with OA is 1.41. The prevalence of OA among T2DM patients and that of T2DM in OA patients was 29.5% and 14.4%, respectively [139]. A meta-analysis study carried out to assess the prevalence of OA in patients with DM revealed a high association between the two, even suggestive of identification of a T2DM-related OA within a metabolic phenotype [140].
Evidences suggest that T2DM elicits a pathological role on OA effected via two important pathways: (1) chronic hyperglycemia, which promotes oxidative stress, bolsters pro-inflammatory cytokines and AGEs production in joint tissues but also decreases the chondrogenic differentiation potential of the various stem cells thereby further decreasing the already impaired cartilage repair in OA; and (2) insulin resistance, which executes its effects both locally and also through low-grade inflammation systemically [138]. Articular chondrocytes are highly glycolytic cells expressing glucose transporters (GLUT 1, 3, and 9) that need a stable glucose supply for maintenance of cellular energy homeostasis [134]. Normal human chondrocytes sense fluctuations in the extracellular glucose levels and accordingly adapt themselves by regulating GLUT-1 synthesis and its lysosomal mediated degradation [141]. This ability is compromised in OA chondrocytes which become incapacitated to adapt to higher extracellular concentrations of glucose vis-à-vis impaired GLUT-1 downregulation leading to accumulation of glucose within the cells. This has a noxious effect on chondrocyte homeostasis and function manifested as increased and prolonged ROS production, advanced glycation end products (AGEs) accumulation, and expression of inflammatory and catabolic mediators including pro-inflammatory cytokines and matrix metalloproteinases [142, 143]. At diabetic glucose concentrations, chondrocytes also become non-responsive to IGF-1 leading to a condition of IGF-1 resistance in chondrocytes [144]. This could also constitute a pathogenic mechanism for cartilage degeneration as IGF-1 exerts anabolic effects in articular cartilage by inducing production of PGs, collagen type II, and other ECM components by the chondrocytes.
ROS conduce to OA pathogenesis by their ability to induce IL-1β, diminish the production and stimulate the degradation of cartilage matrix proteins [145], enhance chondrocyte apoptosis [146], and activate transcription factors like activator protein-1 and NF-κB that play pivotal roles in joint inflammation and cartilage degradation [147]. Accumulation of AGEs in cartilage primarily modifies its mechano-chemical functioning by making the cartilage brittle, promoting matrix stiffness, and making the cartilage more sensitive to mechanical stress resulting in degradation [148]. The accumulated AGEs are also recognized by pattern recognition receptors (PRRs) expressed by the chondrocytes, namely, Receptor for Advanced Glycation Endproducts (RAGE) and TLR-4 which trigger downstream signaling pathways including the MAP kinases and NF-κB pathways leading to a pro-inflammatory and pro-catabolic state of the chondrocytes [149]. AGEs also reduce the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis [150]. Accumulation of AGEs is also higher in the subchondral bone of diabetic patients compared to healthy subjects which may impair the mechanical resistance of subchondral bone and also portray pro-inflammatory effects [138]. Hyperglycemia-induced AGE accumulation in fibroblast-like synoviocytes increased the release of inflammatory factors which in turn induce chondrocyte degradation and promote OA progression [151].
Diabetes also accelerates OA by damaging and deteriorating the functions of the subchondral bone by adversely altering its microarchitecture, chemical composition, and biomechanical properties [152]. In women, higher fasting serum glucose levels were shown to have a positive association with two key predictors of structural OA damage—tibial cartilage volume loss and the occurrence of bone marrow lesions [153]. Together, these evidences indicate that higher levels of glucose adversely affect chondrocytes not only by aiding catabolic responses, but also by modifying their response to anabolic elements ultimately leading to cartilage destruction.
IR and T2DM develop as a consequence of visceral adiposity which presents itself with chronic low-grade systemic inflammation leading to dysregulated joint metabolism precipitating as OA [154]. Insulin receptors are expressed by the chondrocytes which make these cells sensitive to insulin. Insulin has also been identified to induce anabolic effects in a variety of musculoskeletal tissues including cartilage, bone, and tendon promoting cell differentiation, proliferation, and extracellular matrix production [155]. Regardless of the fact that insulin negatively regulates synovial inflammation and catabolism, obese subjects with T2DM develop synovial IR which abates the ability of higher insulin levels to curtail the production of OA-promoting inflammatory and catabolic mediators [138, 156]. In OA, higher insulin levels could facilitate macrophage infiltration and production of chemokines, inhibit autophagy in fibroblast-like synoviocytes, and intensify the inflammatory response by the activation of PI3K/AKT/mTOR/NF-ĸB signaling and a positive feedback loop with the pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) [157]. Also, at supraphysiological insulin concentrations, chondrocytes exhibit impaired autophagy mediated by the increased activity of AKT/mTOR signaling pathway, loss of PG, and increased IL-1β and MMP-13 expression contributing to inflammatory OA-like changes [158]. Impaired autophagy could be one of the mechanisms responsible for accelerated cartilage degradation in diabetes-associated OA patients. Pharmacological intervention to address impaired autophagy may prove effective in preventing T2DM-induced cartilage damage.
Herrero-Beaumont et al. [159] have proposed an additional pathogenic pathway called O-GlcNAcylation to explain the link between OA and diabetes. O-GlcNAcylation is a dynamic post-translational modification where a single O-N-Acetyl-glucosamine residue is incorporated to nucleocytoplasmic and mitochondrial proteins. O-GlcNAcylation is a glucose-dependent process and is involved in regulating cellular activities and the stress response. UDP-GlcNAc serves as the donor for protein GlcNAc, the synthesis of which increases under hyperglycemic conditions mediated by the hexosamine biosynthetic pathway [160]. Findings from studies indicate that the O-GlcNAcylated proteins accumulate in human OA cartilage which could partly induce hypertrophic-like phenotype changes in OA chondrocytes [161], thereby delineating a possible link between diabetes and OA. An integrative view of the pathophysiology of the metabolic-syndrome associated OA is depicted in Fig. 1.
An integrative view of the pathophysiology of metabolic-syndrome associated OA
Hypertension and OA
Hypertension is an important component of MetS and an independent risk factor for cardiovascular and cerebrovascular disease [162]. However, epidemiological studies have now established that OA is more common in subjects with hypertension [163] and is highly likely a key factor in the pathogenesis of MetS-associated OA. In the latest Framingham Osteoarthritis study, the investigators observed that even after adjusting for BMI or body weight, there was a significant association between hypertension and the occurrence of OA [164]. Studies attempting to understand the mechanism behind the role of hypertension in the pathogenesis of OA have centered on vascular pathology leading to subchondral ischemia [165]. Hypertension-induced vasoconstriction over a period of time could reduce flow of blood through the small vessels in the subchondral bone. Also, venous occlusion or microemboli development in subchondral blood vessels can narrow the vessel lumen leading to blockage and reduced blood flow ultimately resulting in subchondral ischemia [166]. The impending pernicious effects of subchondral ischemia are (1) a debilitated nutrient and oxygen exchange across cartilage and bone triggering cartilage degradation and (2) apoptosis of osteocytes in the ischemic regions of subchondral bone which might elicit osteoclastic resorption rendering deprivation of bony support for the above lying cartilage [19, 167]. Joint loading also results in subchondral trabecular loss that leads to cartilage breakdown by favoring cartilage deformation. Subchondral bone remodeling plays an important role in hypertension-mediated joint deterioration in OA. Evidences also show that there could be an involvement of multiple genes in OA and hypertension such as the OPG/RANKL, OPG, and LDRP 6, gene polymorphisms of vitamin D receptor and IL-6 [168]. Recent epidemiological evidence have also ascertained a positive association between hypertension and knee OA of both radiological and symptomatic disease and pain severity, accentuating the significant relationship between hypertension and OA [167, 169]. In addition to a plethora of clinical and epidemiological evidence(s), several in vivo models portraying features of MetS such as UC-Davis-T2DM rats [170], WNIN/Gr-Ob obese rats [32•], Zucker Diabetic Fatty (ZDF) rats [171], obese Spontaneously Hypertensive Heart Failure (SHHFcp/cp) rats [172], diet-induced obese mice, rat, and guinea pig models [173, 174], and T2DM db/db mice [175] have also helped better decipher and establish the association between MetS and OA.
Even as multiple components of metabolic syndrome predispose to OA, optimal management of OA must encompass modification of risk factors through targeted interventions. Obesity/overweight, physical activity, and diet are among the chief modifiable risk factors that could affect the course of OA [176]. Survival analysis from a recent Osteoarthritis Initiative data has concluded that every 1% weight loss was associated with a 2% reduced risk of knee replacement in subjects with clinical knee OA and that public health strategies which include weight loss interventions have the potential to lessen the burden of knee and hip replacement surgery [177]. Furthermore, findings from a recent systematic review carried out to assess the effects of exercise on knee OA revealed that strengthening and aerobic exercises had positive effects on OA patients, and both aquatic and land-based programs improved pain, physical function, and quality of life [178]. Data from the recent Osteoarthritis Initiative also revealed that knee OA progression was inversely associated with a prudent dietary pattern comprising high intake of vegetables, fruits, fish, whole grain, and legumes, while a Western dietary pattern characterized by a high intake of processed/red meats, refined grains, high-fat dairy products, sugar-containing beverages, desserts, and sweets increased the radiographic and symptomatic progress of knee OA [179]. Of late, pharmacological agents such as metformin conventionally used for treating type II diabetes have also been shown to be beneficial in treating OA by inhibiting inflammation, modulating autophagy, countering oxidative stress and reducing pain levels [180, 181], and reducing leptin secretion from adipose tissue [182]. Given the multifactorial etiology of MetS-associated OA, current evidence supports lifestyle modifications as a safe and effective means to alter the parameters of MetS, and also yield promising results for decreasing symptomatic and radiographic knee OA [183].
Conclusion
With an abundance of novel evidence arising out of advancements in preclinical, clinical, and epidemiological studies, there has been a paradigm shift in the way OA pathogenesis is perceived. There is undeniable confirmation that OA is not merely a ‘wear and tear’ disease of the elderly as it has been commonly thought of. Given the alarming rate at which obesity and its allied metabolic perturbations are on the rise globally, the need to address metabolic syndrome and its modifiable risk factors gains preeminence in the holistic approach of metabolic OA management. Chronic low-grade inflammation orchestrated by several adipokines and pro-inflammatory cytokines associated with obesity, dysregulated lipid and glucose homeostasis have been among the chief factors that drive the pathogenesis of OA associated with MetS. The identification of key roles for several metabolic regulators in OA pathogenesis has opened up newer avenues in the recognition of therapeutic targets and the development of novel treatments in addressing metabolic OA.
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Acknowledgements
The authors thank the Department of Health Research, Ministry of Health and Family Welfare, New Delhi for financial support to Samuel Joshua Pragasam Sampath through the DHR – Young Scientist Research Fellowship (DHR – YSS Grant No. YSS/2020/000185/PRCYSS).
Funding
Department of Health Research,Ministry of Health and Family Welfare,New Delhi,India,YSS/2020/000185/PRCYSS,Samuel Joshua Pragasam Sampath
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Sampath, S.J.P., Venkatesan, V., Ghosh, S. et al. Obesity, Metabolic Syndrome, and Osteoarthritis—An Updated Review. Curr Obes Rep 12, 308–331 (2023). https://doi.org/10.1007/s13679-023-00520-5
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DOI: https://doi.org/10.1007/s13679-023-00520-5