Lipid metabolism and osteoarthritis: Lessons from atherosclerosis

Progress in Lipid Research 50 (2011) 133–140

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Review

Lipid metabolism and osteoarthritis: Lessons from atherosclerosis Vasiliki Gkretsi a, Theodora Simopoulou b, Aspasia Tsezou a,b,c,⇑ a

Institute of Biomedical Research and Technology, Center for Research and Technology, Thessaly (CE.RE.TE.TH), 51 Papanastasiou Street, 412 22 Larissa, Greece Laboratory of Cytogenetics and Molecular Genetics, School of Medicine, University of Thessaly, University Hospital of Larissa, Larissa, Greece c Department of Biology, School of Medicine, University of Thessaly, Mezourlo Hill, 41110 Larissa, Greece b

a r t i c l e

i n f o

Article history: Available online 27 November 2010 Keywords: Osteoarthritis Lipid metabolism Atherosclerosis Obesity Adipokines Statins

a b s t r a c t Osteoarthritis (OA) is an age-related degenerative disease comprising the main reason of handicap in the Western world. Interestingly, to date, there are neither available biomarkers for early diagnosis of the disease nor any effective therapy other than symptomatic treatment and joint replacement surgery. OA has long been associated with obesity, mainly due to mechanical overload exerted on the joints. Recent studies however, point to the direction that OA is a metabolic disease, as it also involves non-weight bearing joints. In fact, altered lipid metabolism may be the underlying cause. First, adipokines have been shown to be key regulators of OA pathogenesis. Second, epidemiological studies have shown serum cholesterol to be a risk factor for OA development. Third, lipid deposition in the joint is observed at the early stages of OA before the occurrence of histological changes. Fourth, proteomic analyses have shown an important connection between OA and lipid metabolism. Finally, recent gene expression studies reveal a deregulation of cholesterol influx and efflux and in the expression of lipid metabolism-related genes. Interestingly, lipids and lipid metabolism are known to be implicated in the development and progression of another age-related degenerative disease, atherosclerosis (ATH). Thus, although it is tempting to speculate that the osteoarthritic chondrocyte has been transformed to foam cell, it has not been proven yet. However, this may be an intriguing theory linking ATH and OA, which may open new avenues to novel therapeutic interventions for OA taking advantage of previous knowledge from ATH. Ó 2010 Published by Elsevier Ltd.

Contents 1.

2. 3. 4. 5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Osteoarthritis (OA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Clinical interrelations of OA with cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Are OA and ATH interconnected? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic aspect to OA pathogenesis: adiponectins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Link to lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The burden of dyslipidemia for both ATH and OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statins and OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

134 134 134 134 135 135 136 136 137 138 138

Abbreviations: ATH, atherosclerosis; BMI, body mass index; CHD, coronary heart disease; CIA, collagen induced arthritis; CVD, cardiovascular disease; ECM, extracellular matrix; FDA, Food and Drug Administration; HDL, high density lipoprotein; LDL, low density lipoprotein; LOX-1, lectin-like oxidized low-density lipoprotein receptor 1; LXR, liver X receptor; MMPs, metalloproteinases; NSAID, non-steroidal anti-inflammatory drugs; OA, osteoarthritis; Ox-LDL, oxidized low-density lipoprotein; PUFA, omega-3 (n3) polyunsaturated fatty acids; siRNA, small interference RNA. ⇑ Corresponding author at: Department of Biology, School of Medicine, University of Thessaly, Mezourlo Hill, 41110 Larissa, Greece. Tel.: +30 241350 2557; fax: +30 241350 2558. E-mail addresses: [email protected] (V. Gkretsi), [email protected] (T. Simopoulou), [email protected] (A. Tsezou). 0163-7827/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.plipres.2010.11.001

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1. Introduction 1.1. Osteoarthritis (OA) Osteoarthritis (OA) is the most common form of joint disease, with a preference for older adults [1,2]. According to the United Nations 25% of the Western population aged over 65 will be affected by OA by 2010 [3]. OA aetiology is largely unknown and it is believed to be multifactorial. However, it is thought that mechanical load, obesity, injuries, inflammation of the joints, repetitive motion, and genetic predisposition contribute to excessive loading of the joints leading to the onset of the disease. Unlike other forms of arthritis such as rheumatoid arthritis, there are no available disease-modifying drugs for OA treatment that inhibit or reverse the disease progression, thus limiting the patients’ treatment options to non-steroidal anti-inflammatory drugs (NSAIDs) and joint replacement surgery. In fact, patients are often subjected to multiple surgeries either because multiple joints are affected, or because the prosthetic joint needs to be replaced. All in all, apart from the risks associated with total joint replacement surgery and the adverse effects of NSAIDs, there is evidence of increased mortality among OA patients compared to the general population [4]. Although several potential pharmaceutical targets for OA have been identified, a potent and effective disease-modifying drug has not yet been discovered. A typical example involves the metalloproteinaes (MMPs). Despite the fact that the role of proteinase catabolism in articular cartilage is known, several inhibitors have so far failed [5] to successfully treat OA.

1.2. Clinical interrelations of OA with cardiovascular diseases Evidence exists that OA patients are at higher risk than the general population for developing several additional serious conditions and cardiovascular disease (CVD) in particular. In fact, a number of studies have demonstrated association of increased rates of cardiovascular morbidity in OA patients. Interestingly, Cerhan et al. [6] showed overall cardiovascular mortality to be directly proportional to the extent of radiographic evidence of OA by demonstrating diminished survival in women with an increased number of joint groups affected by OA. Similar results were obtained recently by Chan et al. [7]. Likewise, a Finnish cohort study demonstrated that OA in any finger joint (generally regarded as a marker of ‘‘generalized’’ OA) predicted death from CVD [8], while the presence of advanced thumb carpo-metacarpal OA in men predicted a 32% increased risk of total mortality [9]. Studies on coronary heart disease risk factors in OA compared to non-arthritic controls have shown an adverse coronary heart disease risk profile [10,11], while a significant number of patients with OA and without known CVD had a 10-year risk above 15% and 30% risk levels [12], indicating the need for possible or definite intervention, respectively. A USA national survey suggested that OA patients had a higher prevalence of CVD risk factors compared to individuals without any signs of OA [11]. The simplest explanation for the increased frequency of cardiovascular events among OA patients is that they have greater burden of traditional risk factors compared to the general population, such as advanced age, obesity, poor physical activity, dyslipidemia, hypertension, hyperhomocystineamia, diabetes mellitus [13]; all of which comprise aspects of the metabolic syndrome. Concurrent presence of obesity, diabetes and hypertension compared to healthy individuals resulted in the higher prevalence for hand OA in the Rotterdam study [14]. Furthermore, a recent national US survey including more than 7000 adults over the age of 18 years, compared the prevalence of OA

and metabolic syndrome, in OA patients and controls, to determine whether having OA predicts increased cardiovascular risk [15]. The results of the survey showed that crude prevalence of metabolic syndrome was over twofold higher in OA population regardless of sex or race and that having OA was associated with an over fivefold increased risk of having metabolic syndrome at the age of 43.8 years. The authors concluded that if OA and metabolic syndrome are connected, a diagnosis of OA may serve as a red flag for warning to evaluated CVD risk and allow for more timely primary prevention of CVD [15]. Hypertension, in particular, has been linked to OA since 1975 [16], and has been confirmed recently [14,17] while another part of the development of CVD is the development of atherosclerotic manifestations [18]. This review addresses the similarities and interconnections between OA and ATH and emphasizes the role played by altered lipid metabolism in these two diseases suggesting that knowledge acquired from research on ATH should be applied in OA in the hope of identifying novel biomarkers for early disease diagnosis or more effective means of therapy.

2. Are OA and ATH interconnected? OA and ATH are two seemingly un-connected degenerative chronic diseases that happen to have a high incidence of occurrence in developed countries. Both are silent processes and may remain virtually asymptomatic until decades later, as they are evolving with age and they both bear high economic cost that becomes evident when complications become overt. OA could affect the entire joint including the cartilage, the meniscus, the tendons, the subchondrial bone and the synovial membrane. Nevertheless, cartilage and chondrocytes are the most studied components of the joint [19], since cartilage degeneration is the most prominent change observed in OA. Thus, at the early stages extracellular matrix (ECM) is degraded, several proteinases, growth factors, cytokines, and other inflammatory mediators are activated and osteoarthritic chondrocytes exhibit increased cell proliferation and synthesis of extracellular matrix (ECM) proteins such as type II, IX, and XI collagens as a compensatory mechanism to the catabolic activity taking place [19]. At the later stages of the disease chondrocytes become hypertrophic and articular cartilage is progressively degraded [20]. This results in severe pain, difficulty in moving and executing normal everyday life activities with an immediate effect on the patients’ quality of life. ATH on the other hand, is a process in which white blood cells get activated by an injury or inflammation in the artery wall and move from the bloodstream into the artery wall where they are transformed into foam cells that have the ability to collect fat. Thus, smooth muscle cells, connective elastic tissue, cholesterol and other fatty materials are accumulated in this area of the artery wall forming a hard structure known as atherosclerotic plaque, which thickens the artery wall presenting obstacles to normal blood flow [21,22]. Contrary to OA which is not life-threatening by itself, ATH can have grave consequences for the patients’ life as rupture of the atherosclerotic plaque may lead to heart attack, stroke or even sudden cardiac death. Thus, apart from the fact that both OA and ATH are chronic and degenerative, no other association seems to exist between the two diseases. Interestingly however, increasing scientific evidence points to the opposite direction. In fact, it has been recently hypothesized that atheromatous vascular disease is linked to OA and it is even more important in the progression of OA to severe joint damage than in its initiation [23]. Thus, there are several pieces of evidence to support the association between ATH and OA. First, Z39Ig, a transmembrane protein containing two Ig homology domains, found in foamy macro-

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Fig. 1. A schematic representation of the interconnection between OA and ATH in terms of the events taking place, the ultimate outcome in the patients’ lives, and the potential common underlying mechanisms involved as well as a proposed common therapeutic approach.

phages localized in human carotid atherosclerotic plaques was also found to be expressed in macrophages of the osteoarthritic synovial lining [24]. Second, in an animal model of both chronic antigen-induced arthritis and ATH, it was shown that the onset of chronic arthritis in rabbits with ATH resulted in the local and systemic up-regulation of mediators of tissue inflammation and plaque instability thus aggravating vascular lesions [25]. Another recent study in Apolipoprotein E knock-out mice showing resistance in collagen-induced arthritis (CIA) suggested that articular inflammatory load may comprise a risk factor in vascular pathology [26]. Finally, a recent study by Jonnson et al., demonstrated a linear association between the severity of hand OA and ATH in older women [27]. In this study, also known as the AGES Reykjavik study, the severity of hand OA in women was compared with measures of ATH such as carotid intimal thickness, plaque severity, coronary and aortic calcifications, and reported cardiac and cerebrovascular events. The results of the study showed a strong association between carotid plaque severity and coronary calcifications and hand OA in women but not in men [27]. A general and diagrammatic representation of the interconnection between OA and ATH is shown in Fig. 1. 3. Obesity Obesity represents a significant risk factor for both OA [28,29] and ATH [30,31]. Indeed, in addition to many studies published in the past that linked ATH and obesity, a recent study in an animal model of obesity showed accelerated atherosclerotic plaque formation as a result of high fat diet [32]. Interestingly, in 1998 Toda et al. had supported the idea that decreased body fat is more important for OA prevention and management than body weight loss or other indices of obesity, although they had clearly stated that there is not necessarily a cause and effect relationship [33]. Indeed, in a more recent study, in patients with knee OA, a weight reduction of 10% improved function by 28%. In the same study, low energy diet (3.4 MJ/day) seemed to have an advantage over control diet (5 MJ/day) due to the rapidity of weight loss and a more significant loss of body fat [34]. One of the latest relative studies with almost 40,000 participants, showed that the risk of primary knee and hip joint replace-

ment due to OA is correlated both to adipose mass and central adiposity. More specifically adipose mass measurements (fat mass and percentage fat) are associated with an increased risk of joint replacement 10–15 years after their measurement [35]. Complementary to this, in a study where healthy adults participated, Teichtahl et al. demonstrated that increased levels of obesity and adiposity are associated with an increased annual rate of knee cartilage volume loss [36]. Based on these results one could conclude that weight-loss interventions that reduce body mass, or specifically target a reduction in fat mass, may help to reduce the rate at which cartilage volume is lost, and subsequently the risk of OA. 4. Metabolic aspect to OA pathogenesis: adiponectins Many studies have demonstrated that biomechanical factors mediate the relationship between OA and obesity, possibly via the redistribution of the increased body mass to weight-bearing joints [37,38]. However, the association between obesity and OA in nonweight bearing joints, such as hands, infers a metabolic mechanism [27,39–41]. In fact, recently OA was characterized as a metabolic syndrome disorder [42] giving a new perspective to the disease and the development of potential therapeutics. Recently, the role of adiponectin, resistin and leptin – adiposetissue derived proteins, known as adipokines – has been studied in OA [43,44], beside their established role in obesity, metabolic disorders and ATH. Adiponectin, an adipocyte-derived hormone with known antidiabetic and anti-atherogenic properties was found to be present in OA synovial fluid and articular chondrocytes [45,46]. Moreover, it was shown that adiponectin up-regulates Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) and down-regulates MMP-13, protecting cartilage from degeneration [45]. Furthermore, it has been shown that serum levels of adiponectin are elevated in female patients with erosive OA [47]. All the above-described data suggest that adiponectin is critically involved in OA pathogenesis [48]. Interestingly, adiponectin, resistin and leptin were found to exhibit different patterns of distribution within the joint and the circulating environment [49] with resistin and adiponectin being elevated in serum and leptin being elevated in the synovial fluid of the joint, especially in women. Thus, it could be argued that

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the distribution of adipokines may have local effects in the joint and may account for the high prevalence of OA in women [50–55]. More studies have been performed on the role of leptin in OA. Leptin was initially considered as a balance-keeping hormone of body weight since it inhibits food intake and stimulates energy expenditure although it is also involved in the regulation of immunity, endocrine function, and reproduction operating at the same time in the cytokine network of actions [56,57]. With regard to OA, it has been shown that high circulating levels of leptin [58] and leptin’s expression in OA cartilage [59] correlate with body mass index (BMI) and that the pattern and level of leptin expression is also correlated with the grade of cartilage destruction [58]. In vivo administration of leptin in the joints of rats in one study showed a protective effect on cartilage degeneration characterized by promotion of anabolic functions of chondrocytes [58], while in another more recent study in vivo administration of leptin was associated with catabolic functions including increased expression levels of proteinases (MMP-2, MMP-9, and cathepsin D) and depletion of proteoglycan in cartilage [60]. Most studies though point to the latter [61], as leptin was shown to activate nitric oxide synthase leading to loss of chondrocyte phenotype, induced apoptosis and activation of MMPs all of which exert detrimental effect on articular cartilage [56,62–64]. Another interesting aspect of the effect of leptin in OA was investigated in advanced and minimally affected osteoarthritic cartilage where leptin and leptin’s receptor (Ob-Rb) expression levels were significantly elevated in advanced OA cartilage compared to minimally affected cartilage [59]. Interestingly, the same study demonstrated a catabolic role of leptin treatment on chondrocytes as judged by reduced proliferation accompanied by an induction of IL-1beta production and MMP-9 and MMP-13 protein expression. Furthermore, another study showed the potential of leptin as a therapeutic target for OA as it suggested a correlation between leptin expression and DNA methylation in osteoarthritic cartilage and primary chondrocytes [65]. More specifically, it was demonstrated that leptin silencing by small interference RNA (siRNA) dramatically inhibited MMP-13 expression in osteoarthritic chondrocytes which is a desirable effect in OA therapy as it inhibits cartilage degradation [65]. Moreover, the level of leptin in the synovial fluid of the joint was recently shown to be much higher in OA patients compared to control individuals with no history of OA. In fact, leptin levels in the synovial fluid were much more elevated than in serum [59] and were strongly associated with the radiographic severity of OA [66], indicating a local effect of leptin in articular cartilage and further suggesting that leptin levels in the synovial fluid could be used as an effective quantitative marker for detection of OA. Last but not least, at the genetic level, an association was recently revealed between leptin gene single nucleotide polymorphisms and knee OA susceptibility providing in vivo human evidence for the link between leptin, obesity and osteoarthritis [67]. Together these studies on adipokines and their connection to OA and obesity suggest that they may comprise a critical metabolic link between obesity and OA which further proposes the existence of a metabolic compound in OA.

5. Link to lipid metabolism Early studies by Lippiello et al. specifically proposed a role for lipids in OA [68], which was not surprising considering the fact that osteoarthritic cartilage contains substantial stores of lipid deposits, especially in chondrocytes. Their study showed that there was no change in the cholesterol content and that the distribution profile of individual fatty acids in normal and osteoarthritic cartilage was maintained at a certain level with palmitic, oleic, and lin-

oleic acids representing 85% of the total fatty acids. The levels of total fatty acids and arachidonic acid, however, were significantly elevated in OA samples and the elevated level was associated with increasing histological severity [68]. Moreover, another study linked chondrocyte lipid peroxidation to cartilage matrix protein oxidation and degradation in OA [69], providing more evidence for the role of lipid metabolism in OA. In fact, it has been hypothesized that altered lipid metabolism could account for the diversity of changes observed in OA, leading to a novel approach to pharmacological treatment during the early stages of the disease [70]. Interestingly, it has also been suggested that dietary omega-3 (n3) polyunsaturated fatty acids (PUFAs) affect cartilage composition of articular cartilage [71,72] and have beneficial effects in OA as they are associated with amelioration of OA symptoms, further indicating possible involvement of lipid metabolism in OA pathogenesis [73–75].

6. The burden of dyslipidemia for both ATH and OA A key role in ATH pathogenesis is played by lipids and their metabolism and a great part of the prevention and treatment interventions for CVD are based on this. More specifically, it is known that excessive accumulation of free cholesterol is toxic for cells, and as a result most cells have acquired a tight regulation of influx and efflux pathways so that intracellular cholesterol accumulation is prevented [76]. Thus, once cholesterol is accumulated within cells, its efflux is regulated through reverse cholesterol transport via the ligand-activated transcription factor LXR (liver X receptor) [77]. LXR forms a heterodimer with retinoid X receptor (RXR) and both bind to a promoter sequence of the ATP-binding-cassette transporter A1 (ABCA1) gene, which serves as a lipid pump that effluxes cholesterol and phospholipids from the cells to apolipoprotein A1 [78]. As expected and since reverse cholesterol transport genes regulate intracellular lipid levels, their dysfunction or impaired expression is critical for foam cell formation and thus ATH initiation and progression [79]. To add to the similarities between ATH and OA, several studies suggest that lipids may be involved in OA pathogenesis as well. In early population studies, a positive association was reported between elevated serum cholesterol levels and hand OA in women [80]. Decades later in the Chingford study, hypercholesterolemia was associated with knee OA in women and this association was stronger for bilateral knee disease independent of obesity [17]. Further support in the hypothesis that serum cholesterol is a systemic risk factor for OA gave the Ulm study, a cross-sectional study of patients with knee joint replacement due to OA where an association between high serum cholesterol levels and radiologic evidence of OA in the joints of the hand was reported [81]. This result was also verified recently in a Saudi Arabian study which also indicated correlation between high serum cholesterol level and OA [82]. Finally, a more recent study showed that even Apolipoprotein A1, a lipid transport protein which comprises a major constituent of high-density lipoproteins (HDL), is dramatically elevated in the serum of OA patients compared to healthy individuals [83] while it is significantly lower in the synovial fluid of OA patients compared to rheumatoid arthritis patients. Additionally, apolipoprotein E knock-out mice were proven resistant to the development of collagen-induced arthritis (CIA) [26] regardless of the content of fat in their diet. Thus, based on the above and taking into account the metabolic component in OA pathogenesis, it is obvious that altered lipid metabolism is implicated in the mechanisms responsible for the development of the disease, although the exact details of the mechanism are still missing. Proteomic analyses both in osteoarthritic cartilage and isolated chondrocytes have shown that a great part of the proteins that are

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Fig. 2. Diagram showing the cellular and molecular changes observed in normal and osteoarthritic chondrocytes in relation to cholesterol efflux and leptin, as described in detail in the text. It should be noted that increased or decreased expression of proteins is indicated by smaller or bigger sized letters and boxes. For instance, in osteoarthritic chondrocytes there is increased expression of leptin receptor Ob-Rb and increased accumulation of lipid droplets while at the same time there is dramatic reduction in the expression levels of LXR, ABCA1 and Apolipoprotein A1. All the changes observed in osteoarthritic chondrocytes compared to normal are shown in red color.

differentially expressed in osteoarthritic tissue are related to lipid metabolism such as peroxisome proliferators-activated receptors (PPAR), and Apolipoproteins [84–87]. Moreover, oxidized low-density lipoprotein (Ox-LDL) was detected in the synovial fluid and its receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) was detected in cartilage from both weight-bearing and non-weight-bearing areas, whereas no LOX-1 expression was found in normal cartilage [88]. The presence of this receptor in cartilage indicates that chondrocytes are indeed capable of internalizing lipids [89]. Interestingly, quite recently the expression of genes regulating cholesterol efflux was studied in human osteoarthritic chondrocytes. This study revealed that osteoarthritic chondrocytes contained intracellular lipids deposits and that cholesterol efflux gene expression such as those for Apolipoprotein A1, or liver X receptors (LXR alpha and LXR beta) were dramatically reduced in osteoarthritic articular cartilage samples compared to normal [90]. Similar results on LXR expression in osteoarthritic chondrocytes were presented by Collins-Racie et al. [91]. Tsezou et al., however, additionally showed that treatment of osteoarthritic chondrocytes with the LXR agonist TO-901317 significantly increased Apolipoprotein A1 and ABCA1 expression levels, as well as cholesterol efflux decreasing lipid deposits within the osteoarthritic chnodrocytes [90]. Thus, the LXR-agonist completely reversed the expression of proteins related to cholesterol efflux and cholesterol efflux itself, indicating that LXR agonists could be a novel means for OA therapy. A simple diagram illustrating (at the cellular level) the role of cholesterol efflux and altered lipid metabolism in OA pathogenesis is shown in Fig. 2. 7. Statins and OA The above mentioned studies provide a link between ATH, dyslipidemia and OA, which supports the hypothesis that statins, a

drug class widely used in the treatment of hypercholesterolemia may be a useful tool in OA, as it is becoming clear that these drugs have more than just cholesterol lowering properties as they possess the ability to reduce cardiovascular mortality by means of non-hypolipidemic effects. While there is evidence that statins may present therapeutic potential for OA treatment [23,92], research activity in the field is not very intense. Initial efforts to use statins for OA treatment were in vitro and showed the effect of statins as anti-inflammatory mediators [93]. In fact, based on these results, Beattie et al. examined 745 white females using oral administration of statins for over 8 years for the treatment of OA [94]. The study revealed that patients taking statins showed a non-significant trend toward reduced radiographic progression of hip OA compared to those not taking statins. However, in the same study they observed that statin use was associated with an elevated risk for development of new radiographic evidence of OA, possibly due to stimulation of vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) which contribute to angiogenesis and bone formation [94]. Nevertheless, researchers conducting the study acknowledged that it had several drawbacks since first, statins were administered orally, second, the number of women taking statins was small, and third, the statin intake was neither consistent nor persistent. Statins are widely known for their use in patients with ATH. In fact, metalloproteinase (MMP) inhibition is thought to likely contribute to their mechanism of action, as certain MMPs such as MMP-2 and MMP-9 have been shown in animal studies to be involved in destabilizing the fibrous cap of atherosclerotic plaque, increasing thus the risk of heart attack [95]. Interestingly, MMPs are also involved in the destruction of cartilage. Although the repertoire of MMPs involved in OA may present differences compared to that of the MMPs thought to be involved in ATH, with MMP-13 being the most well-studied in OA, the notion that statins inhibit MMP production in human chondrocytes has been expressed

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[93,96]. Thus, one could speculate that statins may represent a promising therapeutic target for OA treatment. Several studies have been done to test this hypothesis, mainly in cultured cells. More specifically, the study by Lazzerini et al. [97] showed that simvastatin inhibits the production of MMP-3 in chondrocyte cultures in vitro, while two other studies revealed that statins promote apoptosis of synovial fibroblasts from OA patients which is a desirable result in OA treatment [98,99]. Moreover, recent work in the field has confirmed that treatment of osteoarthritic chondrocytes in vitro with atorvastatin produces a significant dose-dependent reduction in IL-1b production accompanied by a decrease in MMP-13 expression level [100]. Interestingly, addition of the mevalonate isoprenoid derivative farnesol reverses the changes in expression levels. This further verifies the idea that lipids are crucially involved in the pathogenesis of OA and that statins reduce cartilage degradation. However, few in vivo studies involving statins have been performed to date. Leung et al. showed in the CIA mouse model of arthritis that intraperitoneal simvastatin reduces the number of arthritic joints and the degree of swelling in a dose dependent manner, while at the same time inhibiting cartilage degradation [101]. Moreover, another study in the same model of arthritis, showed no preventive effect using oral atorvastatin or subcutaneous rosuvastatin [102] although intraperitoneal simvastatin reduced the mean arthritis score and the number of affected paws. The latter however, was used at toxic concentrations and it was accompanied by severe side effects including early death. This difference in the observed effects could be explained by the different routes of statin administration used. Oral, subcutaneous or intraperitoneal administration of statins may not be as effective, as in these cases a small amount of the drug administered is actually reaching the desired point (i.e. joint). This is further demonstrated in a more recent in vivo study in a model of OA in rabbits undergoing bilateral anterior cruciate ligament transaction, which showed that intra-articular administration of mevastatin reduces cartilage degradation in vivo as well as inflammatory markers and proteinase expression in synovial fibroblasts in vitro [103]. Thus, it seems that statins may have therapeutic potential for OA treatment although some finetuning is still needed in the in vivo studies. Therefore, since statins have displayed benefits in modifying the progression of ATH via anti-inflammatory and matrix-stabilizing mechanisms, and since there are several promising in vitro and in vivo data, on the use of statins to treat OA, one could speculate their potential use to treat OA. 8. Conclusions and perspective OA and ATH are two chronic diseases that affect a major part of the population and act silently for years until they become manifested with sometimes grave consequences for the patient’s life. Although there is no cause and effect relationship between the two diseases there certainly exist similarities in their underlying aetiopathogenic factors (see also Fig. 1). Obesity, body fat, fatty acid content, and cholesterol level seem to comprise some of the most important factors of both degenerative diseases bringing lipid metabolism into play for OA as well. Recent studies have implicated altered lipid metabolism in the pathogenesis of OA and it is tempting to envision possible double targeted therapies for both ATH and OA. References [1] Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26–35. [2] Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778–99.

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