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Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)

  • F. Berenbaum
    Correspondence
    Address correspondence and reprint requests to: F. Berenbaum, Department of Rheumatology, Pierre & Marie Curie University, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. Tel: 33-1-49-28-25-20; Fax: 33-1-49-28-25-13.
    Affiliations
    University Pierre & Marie Curie, Paris VI, Sorbonne Universités, 7 quai St-Bernard, 75252 Cedex 5 Paris, France

    Department of Rheumatology, AP-HP Saint-Antoine Hospital, 75012 Paris, France
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Open ArchivePublished:December 20, 2012DOI:https://doi.org/10.1016/j.joca.2012.11.012

      Summary

      Osteoarthritis (OA) has long been considered a “wear and tear” disease leading to loss of cartilage. OA used to be considered the sole consequence of any process leading to increased pressure on one particular joint or fragility of cartilage matrix. Progress in molecular biology in the 1990s has profoundly modified this paradigm. The discovery that many soluble mediators such as cytokines or prostaglandins can increase the production of matrix metalloproteinases by chondrocytes led to the first steps of an “inflammatory” theory. However, it took a decade before synovitis was accepted as a critical feature of OA, and some studies are now opening the way to consider the condition a driver of the OA process. Recent experimental data have shown that subchondral bone may have a substantial role in the OA process, as a mechanical damper, as well as a source of inflammatory mediators implicated in the OA pain process and in the degradation of the deep layer of cartilage. Thus, initially considered cartilage driven, OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium. Low-grade inflammation induced by the metabolic syndrome, innate immunity and inflammaging are some of the more recent arguments in favor of the inflammatory theory of OA and highlighted in this review.

      Keywords

      Osteoarthritis (OA) has long been considered a “wear and tear” disease leading to loss of cartilage. OA used to be considered the sole consequence of any process leading to increased pressure on one particular joint (e.g., overload on weight-bearing joints, anatomical joint incongruency) or fragility of cartilage matrix (genetic alterations of matrix components). This paradigm was mainly based on the observation that chondrocytes, the only cell type present in cartilage, have very low metabolism activity with no ability to repair cartilage. Moreover, unlike all other tissues, articular cartilage, once damaged, cannot respond by a usual inflammatory response because it is non-vascularized and non-innervated.
      Progress in molecular biology in the 1990s has profoundly modified this paradigm. The discovery that many soluble mediators such as cytokines or prostaglandins can increase the production of matrix metalloproteinases (MMPs) by chondrocytes led to the first steps of an “inflammatory” theory. However, it took a decade before synovitis was accepted as a critical feature of OA, and some studies are now opening the way to consider the condition a driver of the OA process. Recent experimental data have shown that subchondral bone may have a substantial role in the OA process, as a mechanical damper, as well as, as a source of inflammatory mediators implicated in the OA pain process and in the degradation of the deep layer of cartilage. Thus, initially considered cartilage driven, OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium
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      (Fig. 1). Interestingly, the source and type of inflammatory mediators may differ by OA phenotype
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      Figure thumbnail gr1
      Fig. 1Systemic effects and potential consequences of OA-derived inflammatory mediators. A proposed novel paradigm for the role of low-grade inflammation in OA. Low-grade inflammation is characterized by the release of inflammatory mediators into the blood during MetS (obesity, insulin resistance, lipid abnormalities, hypertension) or aging (secretory senescence, see text). These inflammatory mediators are deleterious for joint tissues, thus initiating and/or perpetuating the OA process. Once activated, OA joint cells in turn release inflammatory mediators into the joint cavity and eventually into the blood. The mediators amplify the low-grade inflammation, which may induce or accelerate other chronic diseases affected by systemic low-grade inflammation.

      Synovitis (local inflammation) in OA

      Joint swelling is one clinical feature of OA attributed to inflammation and reflecting the presence of synovitis due to thickening of the synovium or to effusion. When patients experience OA flares (night pain, morning stiffness), they usually exhibit in parallel joint effusion, as is seen in classical inflammatory arthropathies such as rheumatoid arthritis (RA)
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      . Systemic high-sensitivity C-reactive protein levels reflect synovial inflammation in OA patients and are associated with level of pain
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      Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis.
      . Interestingly, synovial inflammation frequently occurs in traumatic meniscal injury and is associated with increased pain and dysfunction
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      .
      Why the synovium becomes inflamed in OA remains controversial
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      The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis.
      . The most accepted hypothesis is that, once degraded, cartilage fragments fall into the joint and contact the synovium. Considered foreign bodies, synovial cells react by producing inflammatory mediators, found in synovial fluid. These mediators can activate chondrocytes present in the superficial layer of cartilage, which leads to metalloproteinase synthesis and, eventually, increase cartilage degradation. The mediators can also induce synovial angiogenesis and increase the synthesis of inflammatory cytokines and MMPs by synovial cells themselves (vicious circle). Thus, OA synovitis perpetuates the cartilage degradation.
      More recently, another theory involves synovial tissue as a primary trigger of the OA process. Indeed, many cell types usually present in immunological processes have been described in OA, as bystanders and as actors
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      Alterations of the CD4(+), CD8 (+) T cell subsets, interleukins-1beta, IL-10, IL-17, tumor necrosis factor-alpha and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations.
      . Depleting synovial macrophages with clodronate liposome before inducing a collagenase-induced instability model of OA in mice prevented the generation of MMP-induced neoepitopes into cartilage
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      Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.
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      Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis.
      , which indicates an important role for synovial macrophages in MMP-mediated cartilage damage. Moreover, osteophyte formation was decreased, which suggests that these cells are pivotal for this feature
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      Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis.
      . Synovial Inflammation may drive synovial angiogenesis, linked to OA pain, through macrophage activation
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      Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis.
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      Inflammation and angiogenesis in osteoarthritis.
      . Molecular markers for dendritic cells were detected in the synovium in a post-traumatic rabbit OA model. Interestingly, large numbers of such cells were observed in the early stages after surgery, which suggested their participation in the early stages of OA
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      Dendritic cells of synovium in experimental model of osteoarthritis of rabbits.
      . Suurmond et al. showed an increased expression of interleukin 17 (IL-17) in OA synovial tissue, synovial mast cells being the main IL-17-positive cells
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      Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium.
      .

      Innate immunity as a trigger of local inflammation in OA

      The innate immune system, also known as non-specific immune system, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This system is triggered after the binding of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) on pattern-recognition receptors (PRRs)
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      The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
      . Thus, these responses have been studied as predominant features in multiple non-infectious diseases with tissue injury and/or defective repair. PRRs include membrane-associated PRRs (Toll-like receptors [TLRs], the basic signaling receptors of the innate immune system), cytoplasmic PRRs (nucleotide-binding oligomerization domains [NODs], NALPs, RNA helicases) and secreted PRRs (complement receptors, collectins). PAMPs include bacterial and viral ligands and also extracellular matrix molecules. PAMPs are recognized by TLRs and other PRRs. A pioneer study showed that TLRs are increased in level in OA cartilage lesions
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      The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes.
      . TLR-2 and TLR-4 ligands such as low-molecular-weight hyaluronic acid, fibronectin, tenascin-C and alarmins (S100 proteins, high-mobility group protein B1 [HMGB1]) have been found in OA synovial fluid
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      High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes.
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      Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis.
      . These factors can induce catabolic responses in chondrocytes and/or inflammatory responses in synoviocytes. For example, S100A8 and S100A9 proteins are involved in synovial activation and cartilage destruction, and high levels may predict joint destruction in OA
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      Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.
      . These results are corroborated by a proteomic analysis revealing that proteins from OA synovial fluid can induce macrophage production of inflammatory cytokines via TLR-4 signaling
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      Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14.
      . Interestingly, recent data suggest that these events may occur early in the disease, so innate immunity may be a driver of the OA process. Synovial fluid from patients with early OA cartilage damage showed increased fibroblast-like synoviocyte responses to TLR-2 and TLR-4 ligands
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      Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14.
      . Increased levels of interleukin-15 (IL-15) protein are found in the synovial fluid of early knee OA patients when compared to end-stage OA, and numbers of CD8 cells within the synovial membrane is correlated with MMP-1
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      Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease.
      .
      Another group of proteins involved in innate immunity has recently been highlighted in the context of OA. With proteomic and transcriptomic analyses of synovial fluids and synovial membranes from subjects with OA, Qiang et al. found that the expression and activation of complement is abnormally high in human OA joints
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      Identification of a central role for complement in osteoarthritis.
      . Moreover, with experimental OA-induced in mice genetically deficient in different complement factors or by using specific pharmacological inhibitors, the authors showed that dysregulation of complement in synovial joints may have a key role in OA pathogenesis.
      Innate immunity responses may be triggered by crystals
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      Crystals, inflammation, and osteoarthritis.
      . Calcium pyrophosphate dihydrate and basic calcium phosphate crystals are common in OA joint fluids and tissues
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      Detection of basic calcium phosphate crystals in osteoarthritis.
      . These crystals, along with uric acid, can interact with the NALP-3 inflammasome, an intracellular protein complex involved in IL-1β and IL-18 activation by cleaving pro-caspase-1 to caspase-1
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      • Mayor A.
      • Tardivel A.
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      Gout-associated uric acid crystals activate the NALP3 inflammasome.
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      Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.
      . These processes have been well described in gout, but whether they occur in OA remains debatable
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      Stress-induced cartilage degradation does not depend on NLRP3 inflammasome in osteoarthritis.
      .

      Low-grade systemic inflammation in OA

      Local production of inflammatory mediators are well known to contribute to cartilage degradation and synovial cell activation, but additional data may link these events to a more systemic pathway. In other words, inflammatory events occurring within joint tissues could be reflected outside the joint in plasma and peripheral blood leukocytes (PBLs) of patients with OA. Levels of several inflammatory mediators are higher in OA than healthy sera
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      • Chandra P.E.
      • Lahey L.J.
      • et al.
      Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.
      • Attur M.
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      • Li Z.
      • Krasnokutsky S.
      • Samuels J.
      • et al.
      Inflammatory genomic and plasma biomarkers predict progression of symptomatic knee OA (SKOA).
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      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      . A remarkable study assessed gene expression profiles in PBLs from patients with OA and found a subset with activated PBLs
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      • Greenberg J.
      • Samuels J.
      • et al.
      Increased interleukin-1β gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis.
      . Interestingly, cluster analysis revealed two distinct subgroups: one with increased level of IL-1β and one with normal expression. Patients with the inflammatory “IL-1β signature” had higher pain scores and decreased function and were at higher risk of radiographic progression of OA.
      The risk of hand OA is increased two-fold in obese patients
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      • Stojanovic-Susulic V.
      • DeGroot J.
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      • et al.
      Association between weight or body mass index and hand osteoarthritis: a systematic review.
      . This increased risk cannot be explained by the mechanical effect of overload but can certainly be explained by systemic factors released mainly by abdominal adipose tissue and able to reach and then activate joint cells
      • Pottie P.
      • Presle N.
      • Terlain B.
      • Netter P.
      • Mainard D.
      • Berenbaum F.
      Obesity and osteoarthritis: more complex than predicted!.
      . These systemic factors, called adipokines, have been extensively studied in OA. Among them, leptin, adiponectin, resistin and visfatin/NAMPT have pro- and/or anti-inflammatory properties in OA
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      Adipokines in arthritis: new kids on the block.
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      What's new in our understanding of the role of adipokines in rheumatic diseases?.
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      • et al.
      Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: possible influence on osteoarthritis.
      . Interestingly, recent epidemiological and clinical data have highlighted that a metabolic syndrome (MetS) rather than obesity itself has the greatest impact on the initiation and severity of OA
      • Puenpatom R.A.
      • Victor T.W.
      Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data.
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      Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: a 3-year follow-up of the ROAD study.
      . In that context, it is noteworthy that there is an independent association between carotid intima medial thickness with the prevalence of knee OA (OR 1.7, 1.1–2.7), and carotid plaque with distal interphalangeal OA (OR 1.4, 1.2–1.7)
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      Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam study.
      . The reasons why there is such a link between atherosclerosis and OA remains elusive. One hypothesis relies on the inflammatory theory of atherosclerosis. Several lines of evidence support the hypothesis that oxidized lipids, including oxidized low-density lipoprotein (ox-LDL), are the most likely triggering factors for cytokine production
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      . All these data give strength to the “adipokines theory,” because the concentration of plasma adipokines is known to be associated with MetS
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      Adipokines as novel biomarkers and regulators of the metabolic syndrome.
      . Not unsurprisingly, a study showed an association of serum adipokine concentration and OA severity
      • Yusuf E.
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      Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis.
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      • et al.
      Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis.
      . Moreover, systemic adipokines were found associated with local synovial tissue inflammation
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      • et al.
      Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.
      . Recently, the infrapatellar fat pad, an adipose tissue localized in the knee, was found to be a potential source of adipokines such as IL-6
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      The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review.
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      The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor.
      . Whether these discoveries would lead to “anti-adipokine” therapies remain hypothetical since these molecules participate into many other physiological processes. However, some data coming from pre-clinical studies could open opportunities. An inhibitor of visfatin/nicotinamide phosphoribosyltransferase (NAMPT), FK866, has recently demonstrated anti-arthritic properties
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      Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.
      . Another result supporting the role of adipokines relates on the clinical efficacy of a dramatic weight loss by bariatric surgery of obese patients on knee OA that parallels a decrease of low-grade inflammatory systemic markers
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      Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis.
      .
      A unique study could change the paradigm of the role of inflammation in OA in the near future. Kyrkanides et al. induced OA in mice genetically at risk of Alzheimer disease
      • Kyrkanides S.
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      • Miller J.-N.H.
      • Olschowka M.E.
      • Johnson R.
      • Yang M.
      • et al.
      Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice.
      . OA exacerbated and accelerated the development of neuroinflammation as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques. A likely scenario is that circulating cytokines contribute to brain inflammation and may exacerbate it in the context of Alzheimer disease.
      Thus, OA could be initiated and/or aggravated by the presence of a systemic low-grade inflammation but this study supports also the hypothesis that OA could be at the initiation of distant age-related diseases via a joint release of inflammatory mediators into the blood stream (Fig. 1). Further experimental and epidemiological studies are needed to confirm this provocative hypothesis.

      Aging, inflammation and OA

      Inflammation is triggered by external mediators such as cytokines and proteases, as well as internal cellular mechanisms leading to increased production of inflammatory mediators and lack of elimination of oxidated proteins. These proteins will in turn increase the concentration of reactive oxygen species (ROS) in cells, further adding to the oxidative damage triggering the inflammation
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      • Franceschi C.
      • et al.
      Innate immunity and inflammation in ageing: a key for understanding age-related diseases.
      . Interestingly, oxidative stress can promote cell senescence, and in particular chondrocyte senescence
      • Loeser R.F.
      Aging and osteoarthritis.
      .
      Although OA is a prototypic age-related disease, the specific mechanisms underlying the process remain largely unknown. At the cellular level, senescence can be divided into two main categories: replicative and secretory. Many human cells in culture have a limited proliferative capacity. After a period of vigorous proliferation, the rate of cell division declines (replicative senescence). However, other cell types like chondrocytes have a lower capacity to divide, which leaves little room for replicative senescence. But these cells have high capacity to synthesize soluble mediators. So, secretory senescence should be predominant with aging. This condition has been called the senescence-associated secretory phenotype (SASP) that includes several inflammatory and prodegradative mediators driven by oxidative stress
      • Coppé J.-P.
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      • Krtolica A.
      • Campisi J.
      The senescence-associated secretory phenotype: the dark side of tumor suppression.
      . Interestingly, the SASP is primarily a delayed response to (epi)genomic damage
      • Campisi J.
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      • Kapahi P.
      • Melov S.
      Cellular senescence: a link between cancer and age-related degenerative disease?.
      . Indeed, IL-1β-stimulated MMP-13 chondrocyte production increases with age, suggesting that aging chondrocytes acquire a SASP
      • Forsyth C.B.
      • Cole A.
      • Murphy G.
      • Bienias J.L.
      • Im H.-J.
      • Loeser Jr., R.F.
      Increased matrix metalloproteinase-13 production with aging by human articular chondrocytes in response to catabolic stimuli.
      .
      Another theory relating inflammation, aging and OA is based on the recent discovery that advanced glycation endproducts (AGEs), produced by a non-enzymatic process in aging tissues, weaken cartilage by modifying its mechanical properties. They can trigger chondrocyte activation by binding to specific receptors present at the surface of the chondrocytes, called RAGE (receptors for AGE). This process can lead to an overproduction of proinflammatory cytokines and MMPs
      • Lotz M.
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      • Loeser R.F.
      • Yammani R.R.
      • Carlson C.S.
      • Chen H.
      • Cole A.
      • Im H.-J.
      • et al.
      Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis.
      • Rasheed Z.
      • Akhtar N.
      • Haqqi T.M.
      Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-B in human osteoarthritis chondrocytes.
      .

      Post-menopausal OA and inflammation

      To understand why the incidence of OA increases greatly after menopause, some groups have investigated estrogen regulation. The estrogen receptor is present in chondrocytes, subchondral osteoblasts and synoviocytes
      • Tankó L.B.
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      . Its activation by estrogen derivatives has led to controversial results, depending on their concentration. However, the overall effect predominantly leads to inhibition of the expression and secretion of proinflammatory cytokines such as IL-1 into the joint
      • Richette P.
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      • Tahiri K.
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      • Torre A.
      • Benallaoua M.
      • et al.
      Oestrogens inhibit interleukin 1beta-mediated nitric oxide synthase expression in articular chondrocytes through nuclear factor-kappa B impairment.
      . Moreover, decreased ovarian function is accompanied by a spontaneous increase in level of proinflammatory cytokines in plasma
      • Pfeilschifter J.
      • Köditz R.
      • Pfohl M.
      • Schatz H.
      Changes in proinflammatory cytokine activity after menopause.
      , which may participate in the low-grade inflammation mentioned here previously. However, this suggestion is speculative because the literature is poor on the topic.

      A direct link between mechanics and inflammation: mechanoreceptor signaling

      The controversy about the origin of the OA process, mechanics or inflammation, should be ended soon thanks to recent discoveries in mechanosignaling. Any abnormal mechanical stress applied on a joint (stretch, compression, shear stress, hydrostatic pressure) can be converted into activated intracellular signals in joint cells by mechanoreceptors present at the surface of joint cells (ion channels, integrins)
      • Guilak F.
      Biomechanical factors in osteoarthritis.
      . These signals may eventually lead to the overexpression of inflammatory soluble mediators such as prostaglandins, chemokines and cytokines when a certain threshold is reached
      • Issa R.I.
      • Griffin T.M.
      Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation.
      . This is the case for chondrocytes and for subchondral bone cells present in subchondral bone
      • Stevens A.L.
      • Wishnok J.S.
      • White F.M.
      • Grodzinsky A.J.
      • Tannenbaum S.R.
      Mechanical injury and cytokines cause loss of cartilage integrity and upregulate proteins associated with catabolism, immunity, inflammation, and repair.
      • Chauffier K.
      • Laiguillon M.-C.
      • Bougault C.
      • Gosset M.
      • Priam S.
      • Salvat C.
      • et al.
      Induction of the chemokine IL-8/Kc by the articular cartilage: possible influence on osteoarthritis.
      • Gosset M.
      • Berenbaum F.
      • Levy A.
      • Pigenet A.
      • Thirion S.
      • Saffar J.-L.
      • et al.
      Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene.
      • Sanchez C.
      • Pesesse L.
      • Gabay O.
      • Delcour J.-P.
      • Msika P.
      • Baudouin C.
      • et al.
      Regulation of subchondral bone osteoblast metabolism by cyclic compression.
      . Intracellularly, the conversion of a mechanical signal to the synthesis of inflammatory mediators is mediated by the activation of inducible signaling pathways. Among them, NF-κB and MAPK pathways seem predominant
      • Berenbaum F.
      Signaling transduction: target in osteoarthritis.
      .

      Therapeutical consequences

      It is noteworthy that despite strong experimental studies described in this review and showing a central role of inflammation in OA, the anti-cytokine approach has not yet proven significative improvement in OA symptoms and structure modification. Pilot and controlled studies using anti-IL-1 and anti-TNF molecules have not been convincing yet
      • Verbruggen G.
      • Wittoek R.
      • Vander Cruyssen B.
      • Elewaut D.
      Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.
      • Chevalier X.
      • Goupille P.
      • Beaulieu A.D.
      • Burch F.X.
      • Bensen W.G.
      • Conrozier T.
      • et al.
      Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.
      . However, a very recent open-labeled trial with etanercept is encouraging
      • Maksymowych W.P.
      • Russell A.S.
      • Chiu P.
      • Yan A.
      • Jones N.
      • Clare T.
      • et al.
      Targeting tumor necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee.
      . These disappointing results may be due to the heterogeneity of the OA patients included in these trials, including phenotypes that may have different pathophysiology (Fig. 2).
      Figure thumbnail gr2
      Fig. 2An hypothesis for the role of inflammation in the pathogenesis of OA according to the phenotype. For each phenotype, the main pathway leading to the release of inflammatory mediators by the joint is highlighted. However, some pathways are shared between phenotypes.

      Conclusions

      The literature is rich in data suggesting that inflammatory mediators play a pivotal role in the initiation and perpetuation of the OA process. The source of such mediators would be local from joint cells and systemic from other tissues such as adipose tissue released in blood flow and then reaching the joint via the subchondral bone vasculature. These mediators then have a deleterious effect on cartilage, bone and synovium. By extrapolation, more recent data suggest that locally produced mediators may have an impact on the initiation and perpetuation of other age-related and metabolic diseases. Deciphering these inflammatory pathways is critical for the discovery of disease-modifying OA drugs in the future.

      Author contribution

      F. Berenbaum is the sole contributor to this review.

      Conflict of interest

      No.

      Acknowledgments

      No.

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