What is the difference between osteoarthritis and osteoarthrosis

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
• Inflammation
• Inflammaging
• Metabolic syndrome
• Low-grade inflammation
• Obesity
• Synovitis
• Cytokines
• Adipokines
• Innate immunity

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)

. Pannus-like synovitis may occur, although much more rarely than in RA

. Gadolinium-enhanced MRI and ultrasonography are reliable, valid tools for showing OA synovitis

. Many studies suggest that the presence of synovitis seen by arthroscopy, magnetic resonance imaging (MRI) or ultrasonography may be a surrogate marker of severity and associated with increased risk of radiographic evidence of disease progression

8

• Roemer F.W.
• Guermazi A.
• Felson D.T.
• Niu J.
• Nevitt M.C.
• Crema M.D.
• et al.

Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study.

• Crossref
• PubMed
• Scopus (225)
• Google Scholar

, 

. Systemic high-sensitivity C-reactive protein levels reflect synovial inflammation in OA patients and are associated with level of pain

10

• Stürmer T.
• Brenner H.
• Koenig W.
• Günther K.-P.

Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein.

• Crossref
• PubMed
• Scopus (154)
• Google Scholar

, 

. Interestingly, synovial inflammation frequently occurs in traumatic meniscal injury and is associated with increased pain and dysfunction

12

• Scanzello C.R.
• McKeon B.
• Swaim B.H.
• DiCarlo E.
• Asomugha E.U.
• Kanda V.
• et al.

Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms.

• Crossref
• PubMed
• Scopus (166)
• Google Scholar

.

Why the synovium becomes inflamed in OA remains controversial

. 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

14

• Hussein M.R.
• Fathi N.A.
• El-Din A.M.E.
• Hassan H.I.
• Abdullah F.
• Al-Hakeem E.
• et al.

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.

• Crossref
• PubMed
• Scopus (93)
• Google Scholar

. 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

15

• Blom A.B.
• van Lent P.L.
• Libregts S.
• Holthuysen A.E.
• van der Kraan P.M.
• van Rooijen N.
• et al.

Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.

• Crossref
• PubMed
• Scopus (241)
• Google Scholar

, 

, 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

. Synovial Inflammation may drive synovial angiogenesis, linked to OA pain, through macrophage activation

, 

. 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

. 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

20

• Suurmond J.
• Dorjée A.L.
• Boon M.R.
• Knol E.F.
• Huizinga T.W.J.
• Toes R.E.M.
• et al.

Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium.

• Crossref
• PubMed
• Scopus (75)
• Google Scholar

.

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)

, 

. 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

. 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

, 

25

• García-Arnandis I.
• Guillén M.I.
• Gomar F.
• Pelletier J.-P.
• Martel-Pelletier J.
• Alcaraz M.J.

High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes.

• Crossref
• PubMed
• Scopus (78)
• Google Scholar

, 

26

• van Lent P.L.E.M.
• Blom A.B.
• Schelbergen R.F.P.
• Slöetjes A.
• Lafeber F.P.J.G.
• Lems W.F.
• et al.

Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis.

• Crossref
• PubMed
• Scopus (141)
• Google Scholar

. 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

27

• Sohn D.H.
• Sokolove J.
• Sharpe O.
• Erhart J.C.
• Chandra P.E.
• Lahey L.J.
• et al.

Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

• Crossref
• PubMed
• Scopus (203)
• Google Scholar

. 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

28

• Nair A.
• Kanda V.
• Bush-Joseph C.
• Verma N.
• Chubinskaya S.
• Mikecz K.
• et al.

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.

• Crossref
• PubMed
• Scopus (67)
• Google Scholar

. 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

28

• Nair A.
• Kanda V.
• Bush-Joseph C.
• Verma N.
• Chubinskaya S.
• Mikecz K.
• et al.

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.

• Crossref
• PubMed
• Scopus (67)
• Google Scholar

. 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

.

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

. 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

. Calcium pyrophosphate dihydrate and basic calcium phosphate crystals are common in OA joint fluids and tissues

. 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

, 

34

• Denoble A.E.
• Huffman K.M.
• Stabler T.V.
• Kelly S.J.
• Hershfield M.S.
• McDaniel G.E.
• et al.

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.

• Crossref
• PubMed
• Scopus (172)
• Google Scholar

. These processes have been well described in gout, but whether they occur in OA remains debatable

.

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

27

• Sohn D.H.
• Sokolove J.
• Sharpe O.
• Erhart J.C.
• Chandra P.E.
• Lahey L.J.
• et al.

Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

• Crossref
• PubMed
• Scopus (203)
• Google Scholar

, 

36

• Attur M.
• Statnikov A.
• Aliferis C.F.
• Li Z.
• Krasnokutsky S.
• Samuels J.
• et al.

Inflammatory genomic and plasma biomarkers predict progression of symptomatic knee OA (SKOA).

• PubMed
• Google Scholar

, 

37

• Fernández-Puente P.
• Mateos J.
• Fernández-Costa C.
• Oreiro N.
• Fernández-López C.
• Ruiz-Romero C.
• et al.

Identification of a panel of novel serum osteoarthritis biomarkers.

• Crossref
• PubMed
• Scopus (80)
• Google Scholar

. A remarkable study assessed gene expression profiles in PBLs from patients with OA and found a subset with activated PBLs

38

• Attur M.
• Belitskaya-Lévy I.
• Oh C.
• Krasnokutsky S.
• 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.

• Crossref
• PubMed
• Scopus (106)
• Google Scholar

. 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

39

• Yusuf E.
• Nelissen R.G.
• Ioan-Facsinay A.
• Stojanovic-Susulic V.
• DeGroot J.
• van Osch G.
• et al.

Association between weight or body mass index and hand osteoarthritis: a systematic review.

• Crossref
• PubMed
• Scopus (289)
• Google Scholar

. 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

. 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

, 

, 

43

• Gosset M.
• Berenbaum F.
• Salvat C.
• Sautet A.
• Pigenet A.
• Tahiri K.
• 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.

• Crossref
• PubMed
• Scopus (164)
• Google Scholar

. 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

, 

, 

46

• Yoshimura N.
• Muraki S.
• Oka H.
• Tanaka S.
• Kawaguchi H.
• Nakamura K.
• et al.

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.

• Google Scholar

. 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)

47

• Hoeven T.A.
• Kavousi M.
• Clockaerts S.
• Kerkhof H.J.
• van Meurs J.B.
• Franco O.
• et al.

Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam study.

• PubMed
• Google Scholar

. 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

. All these data give strength to the “adipokines theory,” because the concentration of plasma adipokines is known to be associated with MetS

. Not unsurprisingly, a study showed an association of serum adipokine concentration and OA severity

50

• Yusuf E.
• Ioan-Facsinay A.
• Bijsterbosch J.
• Klein-Wieringa I.
• Kwekkeboom J.
• Slagboom P.E.
• et al.

Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis.

• Crossref
• PubMed
• Scopus (118)
• Google Scholar

, 

51

• Filková M.
• Lišková M.
• Hulejová H.
• Haluzík M.
• Gatterová J.
• Pavelková A.
• et al.

Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis.

• Crossref
• PubMed
• Scopus (106)
• Google Scholar

. Moreover, systemic adipokines were found associated with local synovial tissue inflammation

. 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

, 

54

• Distel E.
• Cadoudal T.
• Durant S.
• Poignard A.
• Chevalier X.
• Benelli C.

The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor.

• Crossref
• PubMed
• Scopus (151)
• Google Scholar

. 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

55

• Busso N.
• Karababa M.
• Nobile M.
• Rolaz A.
• Van Gool F.
• Galli M.
• et al.

Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.

• Crossref
• PubMed
• Scopus (199)
• Google Scholar

. 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

56

• Richette P.
• Poitou C.
• Garnero P.
• Vicaut E.
• Bouillot J.L.
• Lacorte J.M.
• et al.

Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis.

• Crossref
• PubMed
• Scopus (170)
• Google Scholar

.

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

57

• Kyrkanides S.
• Tallents R.H.
• Miller J.-N.H.
• Olschowka M.E.
• Johnson R.
• Yang M.
• et al.

Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice.

• Crossref
• PubMed
• Scopus (67)
• Google Scholar

. 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

58

• Licastro F.
• Candore G.
• Lio D.
• Porcellini E.
• Colonna-Romano G.
• Franceschi C.
• et al.

Innate immunity and inflammation in ageing: a key for understanding age-related diseases.

• Crossref
• PubMed
• Scopus (373)
• Google Scholar

. Interestingly, oxidative stress can promote cell senescence, and in particular chondrocyte senescence

.

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

. Interestingly, the SASP is primarily a delayed response to (epi)genomic damage

61

• Campisi J.
• Andersen J.K.
• Kapahi P.
• Melov S.

Cellular senescence: a link between cancer and age-related degenerative disease?.

• PubMed
• Google Scholar

. Indeed, IL-1β-stimulated MMP-13 chondrocyte production increases with age, suggesting that aging chondrocytes acquire a SASP

62

• 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.

• Crossref
• PubMed
• Scopus (96)
• Google Scholar

.

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

, 

64

• 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.

• Crossref
• PubMed
• Scopus (181)
• Google Scholar

, 

65

• 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.

• Crossref
• PubMed
• Scopus (120)
• Google Scholar

.

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

66

• Tankó L.B.
• Søndergaard B.-C.
• Oestergaard S.
• Karsdal M.A.
• Christiansen C.

An update review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage.

• Crossref
• PubMed
• Scopus (49)
• Google Scholar

. 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

67

• Richette P.
• Dumontier M.-F.
• Tahiri K.
• Widerak M.
• Torre A.
• Benallaoua M.
• et al.

Oestrogens inhibit interleukin 1beta-mediated nitric oxide synthase expression in articular chondrocytes through nuclear factor-kappa B impairment.

• Crossref
• PubMed
• Scopus (31)
• Google Scholar

. Moreover, decreased ovarian function is accompanied by a spontaneous increase in level of proinflammatory cytokines in plasma

, 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)

. These signals may eventually lead to the overexpression of inflammatory soluble mediators such as prostaglandins, chemokines and cytokines when a certain threshold is reached

70

• Issa R.I.
• Griffin T.M.

Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation.

• Google Scholar

. This is the case for chondrocytes and for subchondral bone cells present in subchondral bone

71

• 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.

• Crossref
• PubMed
• Scopus (79)
• Google Scholar

, 

72

• 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.

• Google Scholar

, 

73

• 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.

• Crossref
• PubMed
• Scopus (86)
• Google Scholar

, 

. 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

.

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

76

• 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.

• Crossref
• PubMed
• Scopus (141)
• Google Scholar

, 

77

• 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.

• Crossref
• PubMed
• Scopus (339)
• Google Scholar

. However, a very recent open-labeled trial with etanercept is encouraging

78

• 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.

• Crossref
• PubMed
• Scopus (67)
• Google Scholar

. 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).

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.

• View Large Image
• Figure Viewer
• Download Hi-res image
• Download (PPT)

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.

References

1. • Kapoor M.
   • Martel-Pelletier J.
   • Lajeunesse D.
   • Pelletier J.-P.
   • Fahmi H.

   Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.

   Nat Rev Rheumatol. 2011 Jan; 7: 33-42
2. • Loeser R.F.
   • Goldring S.R.
   • Scanzello C.R.
   • Goldring M.B.

   Osteoarthritis: a disease of the joint as an organ.

   Arthritis Rheum. 2012 Jun; 64: 1697-1707
3. • Goldring M.B.
   • Otero M.

   Inflammation in osteoarthritis.

   Curr Opin Rheumatol. 2011 Sep; 23: 471-478
4. • Bijlsma J.W.J.
   • Berenbaum F.
   • Lafeber F.P.J.G.

   Osteoarthritis: an update with relevance for clinical practice.

   Lancet. 2011 Jun 18; 377: 2115-2126
5. • Sellam J.
   • Berenbaum F.

   Clinical features of osteoarthritis.

   in: Firestein G.S. Budd R.C. Harris Jr., E.D. McInnes I.B. Ruddy S. Sergent J.S. Kelley's Textbook of Rheumatology. Elsevier Inc, Philadelphia2008: 1547-1561
6. • Shibakawa A.
   • Aoki H.
   • Masuko-Hongo K.
   • Kato T.
   • Tanaka M.
   • Nishioka K.
   • et al.

   Presence of pannus-like tissue on osteoarthritic cartilage and its histological character.

   Osteoarthritis Cartilage. 2003 Feb; 11: 133-140
7. • Guermazi A.
   • Roemer F.W.
   • Hayashi D.

   Imaging of osteoarthritis: update from a radiological perspective.

   Curr Opin Rheumatol. 2011 Sep; 23: 484-491
8. • Roemer F.W.
   • Guermazi A.
   • Felson D.T.
   • Niu J.
   • Nevitt M.C.
   • Crema M.D.
   • et al.

   Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study.

   Ann Rheum Dis. 2011 Oct; 70: 1804-1809
9. • Ayral X.
   • Pickering E.H.
   • Woodworth T.G.
   • Mackillop N.
   • Dougados M.

   Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis – results of a 1 year longitudinal arthroscopic study in 422 patients.

   Osteoarthritis Cartilage. 2005 May; 13: 361-367
10. • Stürmer T.
    • Brenner H.
    • Koenig W.
    • Günther K.-P.

    Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein.

    Ann Rheum Dis. 2004 Feb; 63: 200-205
11. • Pearle A.D.
    • Scanzello C.R.
    • George S.
    • Mandl L.A.
    • DiCarlo E.F.
    • Peterson M.
    • et al.

    Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis.

    Osteoarthritis Cartilage. 2007 May; 15: 516-523
12. • Scanzello C.R.
    • McKeon B.
    • Swaim B.H.
    • DiCarlo E.
    • Asomugha E.U.
    • Kanda V.
    • et al.

    Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms.

    Arthritis Rheum. 2011 Feb; 63: 391-400
13. • Sellam J.
    • Berenbaum F.

    The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis.

    Nat Rev Rheumatol. 2010 Nov; 6: 625-635
14. • Hussein M.R.
    • Fathi N.A.
    • El-Din A.M.E.
    • Hassan H.I.
    • Abdullah F.
    • Al-Hakeem E.
    • et al.

    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.

    Pathol Oncol Res. 2008 Sep; 14: 321-328
15. • Blom A.B.
    • van Lent P.L.
    • Libregts S.
    • Holthuysen A.E.
    • van der Kraan P.M.
    • van Rooijen N.
    • et al.

    Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.

    Arthritis Rheum. 2007 Jan; 56: 147-157
16. • Blom A.B.
    • van Lent P.L.E.M.
    • Holthuysen A.E.M.
    • van der Kraan P.M.
    • Roth J.
    • van Rooijen N.
    • et al.

    Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis.

    Osteoarthritis Cartilage. 2004 Aug; 12: 627-635
17. • Mapp P.I.
    • Walsh D.A.

    Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis.

    Nat Rev Rheumatol. 2012 Jul; 8: 390-398
18. • Haywood L.
    • McWilliams D.F.
    • Pearson C.I.
    • Gill S.E.
    • Ganesan A.
    • Wilson D.
    • et al.

    Inflammation and angiogenesis in osteoarthritis.

    Arthritis Rheum. 2003 Aug; 48: 2173-2177
19. • E X.
    • Cao Y.
    • Meng H.
    • Qi Y.
    • Du G.
    • Xu J.
    • et al.

    Dendritic cells of synovium in experimental model of osteoarthritis of rabbits.

    Cell Physiol Biochem. 2012; 30: 23-32
20. • Suurmond J.
    • Dorjée A.L.
    • Boon M.R.
    • Knol E.F.
    • Huizinga T.W.J.
    • Toes R.E.M.
    • et al.

    Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium.

    Arthritis Res Ther. 2011; 13: R150
21. • Gordon S.

    Pattern recognition receptors: doubling up for the innate immune response.

    Cell. 2002 Dec 27; 111: 927-930
22. • Kawai T.
    • Akira S.

    The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.

    Nat Immunol. 2010 May; 11: 373-384
23. • Kim H.A.
    • Cho M.-L.
    • Choi H.Y.
    • Yoon C.S.
    • Jhun J.Y.
    • Oh H.J.
    • et al.

    The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes.

    Arthritis Rheum. 2006 Jul; 54: 2152-2163
24. • Scanzello C.R.
    • Plaas A.
    • Crow M.K.

    Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?.

    Curr Opin Rheumatol. 2008 Sep; 20: 565-572
25. • García-Arnandis I.
    • Guillén M.I.
    • Gomar F.
    • Pelletier J.-P.
    • Martel-Pelletier J.
    • Alcaraz M.J.

    High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes.

    Arthritis Res Ther. 2010; 12: R165
26. • van Lent P.L.E.M.
    • Blom A.B.
    • Schelbergen R.F.P.
    • Slöetjes A.
    • Lafeber F.P.J.G.
    • Lems W.F.
    • et al.

    Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis.

    Arthritis Rheum. 2012 May; 64: 1466-1476
27. • Sohn D.H.
    • Sokolove J.
    • Sharpe O.
    • Erhart J.C.
    • Chandra P.E.
    • Lahey L.J.
    • et al.

    Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

    Arthritis Res Ther. 2012; 14: R7
28. • Nair A.
    • Kanda V.
    • Bush-Joseph C.
    • Verma N.
    • Chubinskaya S.
    • Mikecz K.
    • et al.

    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.

    Arthritis Rheum. 2012 Jul; 64: 2268-2277
29. • Scanzello C.R.
    • Umoh E.
    • Pessler F.
    • Diaz-Torne C.
    • Miles T.
    • Dicarlo E.
    • et al.

    Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease.

    Osteoarthritis Cartilage. 2009 Aug; 17: 1040-1048
30. • Wang Q.
    • Rozelle A.L.
    • Lepus C.M.
    • Scanzello C.R.
    • Song J.J.
    • Larsen D.M.
    • et al.

    Identification of a central role for complement in osteoarthritis.

    Nat Med. 2011 Dec; 17: 1674-1679
31. • Rosenthal A.K.

    Crystals, inflammation, and osteoarthritis.

    Curr Opin Rheumatol. 2011 Mar; 23: 170-173
32. • MacMullan P.
    • McMahon G.
    • McCarthy G.

    Detection of basic calcium phosphate crystals in osteoarthritis.

    Joint Bone Spine. 2011 Jul; 78: 358-363
33. • Martinon F.
    • Pétrilli V.
    • Mayor A.
    • Tardivel A.
    • Tschopp J.

    Gout-associated uric acid crystals activate the NALP3 inflammasome.

    Nature. 2006 Mar 9; 440: 237-241
34. • Denoble A.E.
    • Huffman K.M.
    • Stabler T.V.
    • Kelly S.J.
    • Hershfield M.S.
    • McDaniel G.E.
    • et al.

    Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.

    Proc Natl Acad Sci USA. 2011 Feb 1; 108: 2088-2093
35. • Bougault C.
    • Gosset M.
    • Houard X.
    • Salvat C.
    • Godmann L.
    • Pap T.
    • et al.

    Stress-induced cartilage degradation does not depend on NLRP3 inflammasome in osteoarthritis.

    Arthritis Rheum. 2012 Aug 29; ()//doi.org/10.1002/art.34678
36. • Attur M.
    • Statnikov A.
    • Aliferis C.F.
    • Li Z.
    • Krasnokutsky S.
    • Samuels J.
    • et al.

    Inflammatory genomic and plasma biomarkers predict progression of symptomatic knee OA (SKOA).

    Osteoarthritis Cartilage. 2012 Apr 20; ()
37. • Fernández-Puente P.
    • Mateos J.
    • Fernández-Costa C.
    • Oreiro N.
    • Fernández-López C.
    • Ruiz-Romero C.
    • et al.

    Identification of a panel of novel serum osteoarthritis biomarkers.

    J Proteome Res. 2011 Nov 4; 10: 5095-5101
38. • Attur M.
    • Belitskaya-Lévy I.
    • Oh C.
    • Krasnokutsky S.
    • 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.

    Arthritis Rheum. 2011 Jul; 63: 1908-1917
39. • Yusuf E.
    • Nelissen R.G.
    • Ioan-Facsinay A.
    • Stojanovic-Susulic V.
    • DeGroot J.
    • van Osch G.
    • et al.

    Association between weight or body mass index and hand osteoarthritis: a systematic review.

    Ann Rheum Dis. 2010 Apr; 69: 761-765
40. • Pottie P.
    • Presle N.
    • Terlain B.
    • Netter P.
    • Mainard D.
    • Berenbaum F.

    Obesity and osteoarthritis: more complex than predicted!.

    Ann Rheum Dis. 2006 Nov 1; 65: 1403-1405
41. • Gabay O.
    • Berenbaum F.

    Adipokines in arthritis: new kids on the block.

    Curr Rheumatol Rev. 2009; 5: 226-232
42. • Gómez R.
    • Conde J.
    • Scotece M.
    • Gómez-Reino J.J.
    • Lago F.
    • Gualillo O.

    What's new in our understanding of the role of adipokines in rheumatic diseases?.

    Nat Rev Rheumatol. 2011 Sep; 7: 528-536
43. • Gosset M.
    • Berenbaum F.
    • Salvat C.
    • Sautet A.
    • Pigenet A.
    • Tahiri K.
    • 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.

    Arthritis Rheum. 2008 May; 58: 1399-1409
44. • Puenpatom R.A.
    • Victor T.W.

    Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data.

    Postgrad Med. 2009 Nov; 121: 9-20
45. • Sowers M.
    • Karvonen-Gutierrez C.A.
    • Palmieri-Smith R.
    • Jacobson J.A.
    • Jiang Y.
    • Ashton-Miller J.A.

    Knee osteoarthritis in obese women with cardiometabolic clustering.

    Arthritis Rheum. 2009 Oct 15; 61: 1328-1336
46. • Yoshimura N.
    • Muraki S.
    • Oka H.
    • Tanaka S.
    • Kawaguchi H.
    • Nakamura K.
    • et al.

    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.

    Osteoarthritis Cartilage [Internet]. 2012 Jul 12; ()
47. • Hoeven T.A.
    • Kavousi M.
    • Clockaerts S.
    • Kerkhof H.J.
    • van Meurs J.B.
    • Franco O.
    • et al.

    Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam study.

    Ann Rheum Dis. 2012 May 6; ()
48. • Tedgui A.
    • Mallat Z.

    Cytokines in atherosclerosis: pathogenic and regulatory pathways.

    Physiol Rev. 2006; 86: 515-581
49. • Deng Y.
    • Scherer P.E.

    Adipokines as novel biomarkers and regulators of the metabolic syndrome.

    Ann N Y Acad Sci. 2010 Nov; 1212: E1-E19
50. • Yusuf E.
    • Ioan-Facsinay A.
    • Bijsterbosch J.
    • Klein-Wieringa I.
    • Kwekkeboom J.
    • Slagboom P.E.
    • et al.

    Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis.

    Ann Rheum Dis. 2011 Jul; 70: 1282-1284
51. • Filková M.
    • Lišková M.
    • Hulejová H.
    • Haluzík M.
    • Gatterová J.
    • Pavelková A.
    • et al.

    Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis.

    Ann Rheum Dis. 2009 Feb 1; 68: 295-296
52. • de Boer T.N.
    • van Spil W.E.
    • Huisman A.M.
    • Polak A.A.
    • Bijlsma J.W.J.
    • Lafeber F.P.J.G.
    • et al.

    Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.

    Osteoarthritis Cartilage. 2012 Aug; 20: 846-853
53. • Clockaerts S.
    • Bastiaansen-Jenniskens Y.M.
    • Runhaar J.
    • Van Osch G.J.V.M.
    • Van Offel J.F.
    • Verhaar J.A.N.
    • et al.

    The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review.

    Osteoarthritis Cartilage. 2010 Jul; 18: 876-882
54. • Distel E.
    • Cadoudal T.
    • Durant S.
    • Poignard A.
    • Chevalier X.
    • Benelli C.

    The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor.

    Arthritis Rheum. 2009 Nov; 60: 3374-3377
55. • Busso N.
    • Karababa M.
    • Nobile M.
    • Rolaz A.
    • Van Gool F.
    • Galli M.
    • et al.

    Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.

    PLoS ONE. 2008 May 21; 3: e2267
56. • Richette P.
    • Poitou C.
    • Garnero P.
    • Vicaut E.
    • Bouillot J.L.
    • Lacorte J.M.
    • et al.

    Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis.

    Ann Rheum Dis. 2011 Jan; 70: 139-144
57. • Kyrkanides S.
    • Tallents R.H.
    • Miller J.-N.H.
    • Olschowka M.E.
    • Johnson R.
    • Yang M.
    • et al.

    Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice.

    J Neuroinflammation. 2011; 8: 112
58. • Licastro F.
    • Candore G.
    • Lio D.
    • Porcellini E.
    • Colonna-Romano G.
    • Franceschi C.
    • et al.

    Innate immunity and inflammation in ageing: a key for understanding age-related diseases.

    Immun Ageing. 2005 May 18; 2: 8
59. • Loeser R.F.

    Aging and osteoarthritis.

    Curr Opin Rheumatol. 2011 Sep; 23: 492-496
60. • Coppé J.-P.
    • Desprez P.-Y.
    • Krtolica A.
    • Campisi J.

    The senescence-associated secretory phenotype: the dark side of tumor suppression.

    Annu Rev Pathol. 2010; 5: 99-118
61. • Campisi J.
    • Andersen J.K.
    • Kapahi P.
    • Melov S.

    Cellular senescence: a link between cancer and age-related degenerative disease?.

    Semin Cancer Biol. 2011 Dec; 21: 354-359
62. • 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.

    J Gerontol A Biol Sci Med Sci. 2005 Sep; 60: 1118-1124
63. • Lotz M.
    • Loeser R.F.

    Effects of aging on articular cartilage homeostasis.

    Bone. 2012 Aug; 51: 241-248
64. • 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.

    Arthritis Rheum. 2005 Aug; 52: 2376-2385
65. • 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.

    Rheumatology. 2010 Dec 20; 50: 838-851
66. • Tankó L.B.
    • Søndergaard B.-C.
    • Oestergaard S.
    • Karsdal M.A.
    • Christiansen C.

    An update review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage.

    Climacteric. 2008 Feb; 11: 4-16
67. • Richette P.
    • Dumontier M.-F.
    • Tahiri K.
    • Widerak M.
    • Torre A.
    • Benallaoua M.
    • et al.

    Oestrogens inhibit interleukin 1beta-mediated nitric oxide synthase expression in articular chondrocytes through nuclear factor-kappa B impairment.

    Ann Rheum Dis. 2007 Mar; 66: 345-350
68. • Pfeilschifter J.
    • Köditz R.
    • Pfohl M.
    • Schatz H.

    Changes in proinflammatory cytokine activity after menopause.

    Endocr Rev. 2002 Feb; 23: 90-119
69. • Guilak F.

    Biomechanical factors in osteoarthritis.

    Best Pract Res Clin Rheumatol. 2011 Dec; 25: 815-823
70. • Issa R.I.
    • Griffin T.M.

    Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation.

    Pathobiol Aging Age Relat Dis [Internet]. 2012 May 9; 2 ()
71. • 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.

    Mol Cell Proteomics. 2009 Jul; 8: 1475-1489
72. • 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.

    Joint Bone Spine [Internet]. 2012 Feb 15; ()
73. • 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.

    Arthritis Res Ther. 2006; 8: R135
74. • Sanchez C.
    • Pesesse L.
    • Gabay O.
    • Delcour J.-P.
    • Msika P.
    • Baudouin C.
    • et al.

    Regulation of subchondral bone osteoblast metabolism by cyclic compression.

    Arthritis Rheum. 2012 Apr; 64: 1193-1203
75. • Berenbaum F.

    Signaling transduction: target in osteoarthritis.

    Curr Opin Rheumatol. 2004 Sep; 16: 616-622
76. • 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.

    Ann Rheum Dis. 2012 Jun; 71 (): 891-898
77. • 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.

    Arthritis Rheum. 2009 Mar 15; 61: 344-352
78. • 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.

    Arthritis Res Ther. 2012 Oct 4; 14: R206

Article Info

Related Articles