Joint injury and osteoarthritis: soluble mediators in the course and treatment of cartilage...

435ISSN 1750-743XImmunotherapy (2009) 1(3), 435–44510.2217/IMT.09.14 © 2009 Future Medicine Ltd

Review

Joint injury and osteoarthritis: soluble mediators in the course and treatment of cartilage pathology

Cytokines provide a network controlling both innate and specific immune responses [1]. In addi-tion, they may be involved in tissue degradation, for example, during remodeling of the periodontal ligament [2,3], wound healing [4], corneal destruc-tion following keratitis [5] or bone loss during osteolytic pathologies [6]. In cartilage pathology, the relatively low turnover and remodeling of car-tilage matrix components [7] is disturbed, result-ing in a net loss of cartilage matrix components and deterioration of structural and functional properties of the cartilage [8]. Cytokines contrib-ute to this process by stimulation and produc-tion of proteolytic enzymes and other catabolic cytokines [9], or by inhibiting proteoglycan [10] or collagen synthesis [11]. In rheumatoid arthritis (RA), increased levels of proinflammatory cyto-kines in synovial fluid (SF) as compared with healthy SF [12,13] correlated with disease sever-ity [14]. Several cytokine-modulating therapies proved effective in reducing RA symptoms and disease progression [15–17]. Cytokines are also c onsidered to play an important part in the pathogenesis and progression of osteoarthritis (OA) [18–20]. In contrast with RA, which is con-sidered a chronic autoimmune disease [21], OA is more a ‘wear-related’ degenerative disorder. Moreover, the onset of OA can be accelerated after previous injury to the joint [22–25].

This review aims to discuss the role of cyto-kines in OA, and in traumatic joint injuries that predispose to development of early OA.

Players in the intra-articular environment � Cytokines

Cytokines are a category of soluble or cell surface molecules that play a role in cellular communica-tion through paracrine, autocrine and endocrine signaling [1]. In the intra-articular environment, cytokines and growth factors may diffuse from the SF towards chondrocytes, where they may bind to the cell surface and stimulate or inhibit the release of other proteins. Vice versa, chondro-cytes release cytokines and growth factors into the surrounding matrix, which are transferred into the SF in part through fluid flow generated by hydrostatic pressure in the course of load-ing the joint [9]. Although the majority of cyto-kines exert multiple effects on cartilage and are involved in a balance of stimulatory as well as inhibitory effects, a division can be made between cartilage-degrading, proinflammatory cytokines (catabolic, or ‘chondrodestructive’), cytokines with both destructive as well as protective func-tions (‘chondro modulatory’) [7] and cartilage-pro-tecting, anti-inflammatory cytokines (anabolic, a nticatabolic or ‘chondroprotective’) (Table 1).

Of the chondrodestructive cytokines, IL-1b

[26,27], TNF-a [28] and their synergistic inter-action have been studied most thoroughly [29,30]. These cytokines stimulate upregulation of vari-ous cartilage-degrading matrix-metalloprotein-ases (MMPs) [31], a process that leads to cleavage and subsequent loss of proteoglycans from the

Osteoarthritis is a disabling disease of the aging generation, which results in loss of quality of life and increased healthcare costs. Cytokines appear to play an important role in the cartilaginous degeneration characterizing the pathological process. Increasing experience is being gained with cytokine-modulating therapies aimed at interfering with effects of chondrodegradative cytokines in the synovial fluid. Although in vitro and in vivo effectiveness of several of these therapies has been demonstrated, clinical effectiveness remains disputable, which may be related to the low levels of inflammatory cytokines found in osteoarthritic joints. By contrast, directly after joint trauma, which has been shown to predipose to early osteoarthritis, synovial fluid cytokine levels are strongly increased. Cytokine-modulating therapies, however, have hardly been considered for this indication. Increased knowledge of intra-articular soluble mediators correlating with cartilage pathology will lead to further development of cytokine-modulating products and, eventually, to effective inhibition of cartilage degeneration, in both the osteoarthritic as well as injured joints.

Keywords: cartilage � cytokine � intra-articular trauma � osteoarthritis � synovial fluid

Marijn Rutgers1, Daniël BF Saris1, Kiem Gie Auw Yang1, Wouter JA Dhert1,2 & Laura B Creemers1† †Author for correspondence: 1University Medical Center Utrecht, Department of Orthopaedics, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsTel.: +31 887 558 077Fax: +31 302 510 [email protected] of Veterinary Medicine, Utrecht University, The Netherlands

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extracellular matrix (ECM), while on the other hand, proteoglycan synthesis is inhibited [9,32]. IL-1a and IL-1b exhibit an amino acid homology of 22% and both bind to the biologically active IL-1 receptor (IL-1R), which leads to transcrip-tion of many proinflammatory genes, including IL‑6 and IL‑8 [33]. Although not as frequently studied as IL-1b, IL-1a is also present in OA SF, albeit at low concentrations [34]. Both cytokines are thought to exert more or less similar effects in cartilage degeneration [35] and are used inter-changeably in research. In this review, IL-1 may refer to either.

Other cytokines with chondrodestructive effects in the intra-articular environment are IFN-g [36], IL-17 [37] and oncostatin-M [38], which were shown to act synergistically with IL-1 in stimulation of production of MMPs and aggre-canases [39]. IL-7 production by osteo arthritic chondrocytes is higher in comparison with healthy chondrocytes [40] and may be involved in fibronectin fragment (Fn-f)-mediated osteo-arthritic degeneration. IL-8 has been shown to promote release of IL-6 [29] and promotes hyper-trophic differentiation [41]. Leukocyte-inhibitory factor (LIF), produced by activated T cells in the synovium, has been shown to enhance IL-1b and IL-8 production in chondrocytes [42].

Chondrodestructive [43] as well as chon-droprotective [29] actions have been described of IL-6. Its ‘chondromodulatory’ effects are mediated through increased production and attraction of inflammatory cells [44] on the one hand, and through stimulation of production of TGF-b [45] and tissue inhibitor of metallo-proteinases (TIMP)-1 [46] on the other hand. IL-6 production is stimulated by IL-1b [29,44]. Basic FGF (bFGF) may inhibit IGF-1-mediated proteoglycan production [47] and induce MMP expression [48], although it may also stimulate chondrocyte proliferation [49] as well as TIMP-1 production [48].

Anti-inflammatory cytokines, such as IL-4, -10 and -13 [50], were shown to have various effects, including inhibition of IL-1 and TNF-a secretion and stimulation of IL-1 receptor antag-onist (IL-1RA/IRAP) expression. IL-1RA com-petes with IL-1 in binding to the IL-1 receptor, and prevention of IL-1 binding inhibits activa-tion of target cells [33], thus inhibiting cartilage degradation (Table 1) [51–54]. Growth factors may also mediate proliferation or differentiation of chondrocytes. TGF-b, a so-called cysteine-knot cytokine [55], stimulates IL-1RA expression and proliferation and differentiation of chondrocytes

[56,57]; however, only few studies report on the presence of TGF-b in the intra-articular envi-ronment [12,58]. At high concentrations, TGF-b may lead to osteophyte formation [59]. IGF is considered as an important mediator in the repair of cartilage defects [60,61] as it is a potent mitogen and differentiation factor steering progenitor cells towards a cartilaginous path-way [62,63]. Osteoprotegerin [64,65] was found to stimulate IL-1RA expression, and increased levels have been reported in OA [66].

extracellular cartilage matrixIn addition to chondrocytes, cartilage consists of water, collagens and proteoglycans (the major constituents of the ECM) [67]. Proteoglycans are composed of a protein core with covalently bound glycosaminoglycan side chains, of which the most important are chondroitin sulfate and keratan sulfate [68]. Hyaluronic acid (HA) is an unsulfated glycosaminoglycan and, although it is not covalently bound to the protein core and thus not part of a proteoglycan, it is involved in forma-tion of proteoglycan aggregates through aggre-can–HA-link protein complexes [9]. Exchange of low-molecular-weight components (<20 kDa) between the cartilage matrix and SF is dependent on biomechanical loading [68]. However, proteo-lytic activity (observed in normal and in degen-erative cartilage) enables other, larger matrix components, such as proteoglycans and HA, to be cleaved into smaller fragments and released into the SF [9]. Fn-fs released following proteolytic activity play a direct role in cartilage turnover by either enhancing cartilage anabolic activity (at low concentrations) or stimulation of catabolic c ytokine release [40], upregulation of MMP e xpression and enhancing degradation of proteo-glycans [69]. Increased levels of Fn-fs in SF may be considered as a ‘signal’ of increased catabolism, and have been observed in patients with RA as well as OA [70]. In addition to cytokine-mediated car-tilage degeneration, it was recently demonstrated

Table 1. Chondrodestructive (proinflammatory), chondromodulatory and chondroprotective (anti-inflammatory, anabolic or anticatabolic) cytokines in the intra-articular environment.

Chondrodestructive Chondromodulatory Chondroprotective

IL-1a, IL-1b IL-6 IL-1RA

TNF-a Basic FGF IL-4

IL-7 IL-10

IL-8 IL-13

IL-17 TGF-bOncostatin M IGF-1

IFN-g Osteoprotegerin

Leukocyte-inhibitory factor

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Joint injury & osteoarthritis Review

that activation of the discoidin domain receptor (DDR)-2 by native collagen plays a role through increased expression of the cartilage-degrading MMP-13 in cultured chondrocytes [71]. In addi-tion, DDR-2 protein was increased at the immu-nohistochemical level in the femoral heads of OA patients [72]. Of course, it cannot be excluded as yet that this activation of MMP-13 expression is mediated through autocrine cytokine signaling.

synoviumSynovial tissue consists of a synovial membrane (facing the joint capsule) and a fibrous layer con-taining loose connective tissue [9] and is the main contributor to changes in SF composition [73]. The synovial membrane consists of one or more layers of epitheloid cells, which covers a layer of fibrous tissue containing type A and type B cells [74]. The A cells resemble macrophages and can be released from the synovial membrane into the SF. The majority of the cells in the synovial membrane, however, are ‘B’ cells, which resem-ble fibroblasts and secrete proteins, glycoproteins and hyaluronic acid into the SF [75]. The fibrous tissue layer contains adipocytes, mast cells, nerve fibres, vascular endothelial cells and, occasion-ally, lymphocytes. Capillaries in the fibrous t issue layer enable exchange of nutrients.

synovial fluidThe composition and volume of SF varies between individuals and between different joints within an individual. The average healthy human knee con-tains between 1.1 and 6.7 ml [76,77] of SF, which is distributed over the surfaces of femoral and tib-ial articulating surfaces in a layer just 10–20 µm thick [9], throughout the joint cavity. Although leukocytes are usually only present at low con-centrations in SF, they have also been mentioned to contribute to intra-articular cytokine and growth factor levels [78]. Traumatic changes to the joint, for example rupture of an anterior cru-ciate ligament, meniscal tears or dis location of a cartilage or osteochondritis dissecans fragment, may change SF composition, either gradually following increased SF production by type B synovial cells, or rapidly through intra-articular hemorrhaging. In contrast to the relatively acel-lular healthy SF, blood contains high amounts of leukocytes, as well as erythrocytes and throm-bocytes. Breaching of the blood–SF barrier may affect SF composition, not only through entrance of erythrocytes, leukocytes and monocytes into the joint and subsequent cartilaginous damage

[79], but also through the presence of proinflam-matory cytokines in blood (Table 2).

synovial fluid content in oA The osteoarthritic joint demonstrates changes in cartilage, synovium, subchondral bone and SF [9,80]. Expression of IL-1 in chondrocytes is increased at the mRNA [81] level as well at the immunohistochemical level [82], but expression in the synovial membrane does not seem higher than in healthy individuals [80,83]. Although IL-1b is usually considered an important medi-ator for the OA development, low (<10 pg/ml) or undetectable IL-1b levels were found in sev-eral studies focusing on cytokine levels in SF of OA patients [12,78,84,85].

In general, the role of IL-1 in OA may have been overstated. Although it is commonly sug-gested that IL-1 exerts its effects at very low concentrations, either or not by synergy with other proinflammatory cytokines, there is not much support for this assumption. While there are studies that mention IL-1b concentrations of as low as 10 pg/ml to be capable of inhib-iting proteoglycan synthesis in vitro [86,87], commonly, IL-1b concentrations of at least 1000 pg/ml were necessary to induce c artilage damage. Studies demonstrating synergistic effects of IL-1b with IFN-g [36], TNF-a [30], IL-17 [88] or oncostatin-M [38] also depart from

Table 2. Average cytokine levels of chondroprotective, chondromodulatory and chondrodestructive cytokines in serum of healthy patients, and in synovial fluid of healthy and osteoarthritis patients.

Cytokine Healthy serum (pg/ml)

ref. synovial fluid (pg/ml)

ref.

IL-1 <5.0 [129,138] <3.0 [84,96,139]

IL-4 <20 [123,140] 0.1 [139]

IL-6 <12.5 [129,140,141] 0.5 (0.7) [139]

IL-7 <10.0 [142] 1.1 (2)* [143]

IL-8 <15 [144] 89.9 (45.88) * [84]

IL-10 <10 [129] 21 (2.0) * [80]

IL-13 <20 [145] 0.4 (1.4) * [Rutgers M, Unpublished Data]

IL-17 39.9 (2.3) [146] 0 (0–84) * [147]

IFN-g <15 [145] 16.0* [12]

TNF-a <3.0 [140] <5.0 [96,139]

OPG 5.4–6.5 [148] 8935 (9303) * [Rutgers M, Unpublished Data]

OSM <1.0 [141] 4.5 (2–20) * [149,150]

LIF 3.8 (3.4) [141] <15.0* [150]

IL-1RA 73–175 [123,129] 614 (292–1951) * [128]

TGF-b 20580 [151] 581 (257) * [Rutgers M, Unpublished Data]

IGF-1 186000 [152] 82000 (10000) * [153]*Levels were obtained of osteoarthritis synovial fluid.LIF: Leukocyte-inhibitory factor; OPG: Osteoprotegerin; OSM: Oncostatin M.



much higher IL-1b concentrations (100 pg/ml and higher) than in OA SF, which does not support a synergistic effect at low IL-1b levels. Animal models using IL-1b to induce OA also depart from concentrations 1000-fold higher than those found in OA SF [89,90], further supporting the need for high levels to induce intra-articular effects. In addition, study of OA in animals usually involves OA models in which onset of OA is ‘accelerated’, based on surgical [91] or biochemical [92] destruction of part of the cartilage, complete or incomplete meniscectomy [93] or transsection of a cruciate ligament [94,95]. Depending on the time after ‘induction’ of OA, this ‘OA model’ may, in fact, resemble a post-trauma situation rather than an OA s etting. Thus, the in vitro and in vivo models used for OA may not adequately simu-late human OA and overstate the importance of IL-1b. Similar remarks can be made regarding TNF-a, which is also low in OA SF [78].

In addition to IL-1a, increased production of IL-8 and IL-10 was observed in synovial membranes as well as in the cartilage and sub-chondral bone of patients with OA, while sub-chondral bone also expressed TNF-a, MMP-3, MMP-9 and TIMP-1 [80]. However, major increases in SF cytokine levels, as observed in patients with RA, are not observed in OA

[12,34,78,96]. It may, therefore, be that other SF components are responsible for cartilage degen-eration in OA, either alone or in combination with earlier mentioned cytokines. Although the OA SF concentrations of IL-1b and TNF-a alone do not seem high enough to induce cartilage degeneration, SF of patients with c hronically injured knees inhibited chondro-genesis in a chick limb bud bioassay, while SF of patients with acutely injured knees s timulated chondrogenesis [97].

synovial fluid content in acute traumaAcute trauma is associated with higher SF cytokine levels than the low levels found in OA patients. In vivo, intra-articular cytokine level changes following trauma have been studied following naturally acquired articular injuries [98–100], immobilization of a joint [101], biochemically induced injury [102], or mechani-cally induced intra-articular trauma [61,103]. In patients, cytokine levels after trauma have often been studied following rupture of the anterior cruciate ligament [25,104,105] or following menis-cus or cartilage trauma [97]. In both in vivo and clinical studies, high levels of a variety of cytokines were seen following intra-articular

trauma, often followed by a gradual decrease. In animals, IL-6 levels most frequently increased [98,100] as well as IL-1b, TNF-a, MMP-3 [98] and TGF-b [103]. In humans, IL-6 [25,104,105], IL-1RA [25,104,106], IL-1b [104,106], IL-8 [25,104], IL-10 and TNF-a [104] have been reported to increase following injury. It is unclear whether these acute post-traumatic changes affect car-tilage turnover in a positive [97] or negative way [107], or whether this implicates an initial repair response followed by a ‘turning point’, after which the environment of the chronically injured joint becomes u nfavorable for cartilage integrity (Figure 1) [97].

Therapies � Current treatments for OA

When a patient with OA seeks treatment, symp-tomatic treatment will be attempted first. Of the oral symptomatic therapies, nonsteroidal anti-inflammatory drugs (NSAIDs) [108] and cyclo-oxygenase (COX)-2-specific inhibitors have proven to be effective in reduction of OA symp-toms, while COX-2 inhibitors also demonstrate chondroprotective actions [109,110]. Although COX-2-specific inhibitors are associated with a lower incidence of gastrointestinal complaints than NSAIDs [111], they are associated with a higher cardiovascular morbidity [112] and, thus, are currently prescribed less frequently.

When unsuccessful, disease-modifying OA drugs may be applied in specific patient popu-lations. In OA patients, the combination of oral glucosamine and chondroitin sulfate was more effective in reduction of OA symptoms than placebo, in patients with moderate-to-severe knee pain [113]. Although the evidence for clinical effectiveness of HA treatment in OA is conflicting [114,115], it currently seems that intra-articular HA supplementation is compa-rable in efficacy to systemic forms of active intervention (NSAIDs and physical therapy) but with more prolonged effects than intra-articular corticosteroids for patients with OA of the knee [116]. Although each intra-articular injection of course poses a risk of infection, this risk is considered extremely low (4.6 per 100,000 injections) [117]. In the acute post-trauma setting, improved rehabilitation after ACL reconstruction was demonstrated after intra-articular administration of HA [118].

When symptomatic treatments or treat-ments aiming to restore SF viscosity or supple-ment ECM components are unsuccessful in reduction of OA symptoms, the final ‘golden s tandard’ is surgical joint replacement.



Future therapies: cytokine-modulating therapiesIn RA, targeting of IL-1 and TNF-a proved s uccessful for reduction of disease-related symptoms [15,16]. In OA, inhibition of cartilage degradation was most frequently attempted by targeting IL-1 [119–121]. In vivo, this did seem successful as reduction of OA symptoms, histo-logical parameters and preservation of articular cartilage quality were demonstrated after intra-articular injection of synoviocytes transduced with the IL‑1RA gene in equine and canine OA models [52,122], and IL‑1RA plasmids into a rabbit knee joint with OA induced by meniscectomy. However, in the only clinical OA trial carried out until now, intra-articular injection of recom-binant IL-1RA did not lead to improvement of OA symptoms [121]. Thus far, no compelling evi-dence exists that IL-1RA therapy is effective for treatment of OA in human patients.

A more complex treatment based on intra-articular IL-1RA administration is Orthokine®. Autologous conditioned serum (ACS) is pre-pared by in vitro incubation of the patient’s whole blood in the presence of glass beads, and the resulting product, containing increased lev-els of IL-1RA as well as IL-4 and IL-10 [123], is injected into the joint. Although infrequently investigated, in vivo studies [52,124] examining the effect of Orthokine on OA, and clinical stud-ies [120,125] comparing Orthokine with HA or

placebo demonstrate either little or moderate improvement of OA symptoms. On the other hand, in the study demonstrating the greatest improvement of OA symptoms, the Orthokine-treated cohort was injected with ACS six-times while the placebo and HA cohort were injected only three-times [120]. In this particular study, more frequent injections may have led to a greater improvement in OA symptoms for two reasons. First, a regession ana lysis of 174 ran-domized, controlled OA trials demonstrated that placebo effects increase significantly with increased invasiveness of a treatment procedure (i.e., ‘injection’ in contrast to, for example, an oral therapy) [126]. Thus, the additional injec-tions during ACS treatment may have caused an improvement in OA symptoms merely due to the ‘invasiveness’ of the treatment. Second, as joint lavage proved successful for reduction of OA symptoms in rabbits with surgically induced OA [127], the three additional injec-tions may have been responsible for a ‘lavaging’ effect, thus also resulting in improvement of OA symptoms. The exact composition of the intra-articular injected Orthokine, and thus the basis for the in vivo mechanisms responsible for clinically observed effects, is unknown [119,124].

Although several IL-1RA-based therapies focus on the role of IL-1, their therapeutical relevance may be discussed. IL-1RA levels in OA SF (614 pg/ml [128]) may already be high

Synovium

Synovial fluid

Extracellular cartilage matrix

Activated T cells

Cartilage degradation

Chondrocyte

Fibronectin fragments

IL-17, OSM, OPG, IFN-γ

NOMMP

TIMP

IL-1β, TNF-α, IL-6, IL-7, IL-8, LIF

TGF-β, IGF-β, FGFIL-1RA, IL-4, IL-10, IL-13

IL-1RA, IL-4, IL-10, IL-13, OPG, bFGFIL-1β, TNF-α, IL-6, IL-7, IL-8, LIF

Synovial fibroblasts

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Figure 1. Cytokines in the intra-articular environment. LIF: Leukocyte-inhibitory factor; MMP: Matrix metalloproteinase; NO: Nitric oxide; OPG: Osteoprotegerin; OSM: Oncostatin M; TIMP: Tissue inhibitor of matrix metalloproteinase.



enough to block endogenous IL-1b [51], and it may not therefore be necessary to elevate this baseline level exogenously, as for example by using ACS (2015 pg/ml [129] and 10254 pg/ml [123]) IL-1RA. Moreover, exogenously added IL-1RA may hardly be available to the cartilage due to fast clearance from the joint. Although the theory behind ACS preparation and its effects seem interesting, the lack of knowledge on exact composition of the product or in vivo clinical effects demands for further investigation before broad clinical application.

Although TNF-a inhibition has gained a definite place in RA treatment [130], only a few reports exist on successful improvement of OA symptoms in patients treated with TNF-a inhibitors [131,132]. Osteoarthitic SF and osteo-arthitic synovium supernatants upregulated p55 TNF-a receptors in human chondrocytes

[133]. TNF-a antagonists decreased production of TNF-a by rabbit synovial cells in vitro, and suppressed TNF-a-mediated nitric oxide (NO) production while stimulating IL-1RA synthesis

[134]. As TNF-a levels are strongly elevated in SF after trauma, TNF-a therapy in orthopedics may be promising for intra-articular trauma. However, TNF-a therapy may increase the risk of infections and malignancies [135].

Future perspectiveThere is very little evidence regarding effective-ness of the few existing cytokine-modulating therapies for treatment of OA. This may, in part, be due to the ability of the intra-articular injected substances to in fact reach the target cells and thus mediate their protective effects, or may implicate that chondrodestructive cytokines in accordance with their low levels of in osteo-arthritic SF do not play a major role in main-tenance of the degenerative process. However, as cytokine-modulating therapies may inhibit

further disease progression, it is desirable that further knowledge is gained. Until that time, one may still consider NSAIDs, the combina-tion of glucosamine and chondroitin sulfate, or HA, as therapy.

Current cytokine-modulating therapies may be considered for application after an intra-articular injury in addition to their application for OA, as a ‘normal’ protective intra-articular environment may turn into a chondrodestructive environment with high levels of chondroprotective as well as chondrodegradative cytokines, predisposing to early onset OA after trauma. Studies evaluating the effectiveness of, and determining the medical indication for, these therapies for ‘post-trauma’ may be facilitated by noninvasive methods to depict cartilage qualitative characteristics. An important development in this field has been the introduction of the delayed gadolinium-enhanced MRI of cartilage, which depicts intra-articular proteoglycan distribution without having to per-form an invasive procedure such as a biopsy or arthroscopy [136,137].

The panel of cytokines present in the joint as well as knowledge of their effects is currently expanding. More knowledge on the character-istics of SF will finally optimize effectiveness of cartilage-preserving therapies.

Financial & competing interests disclosureMarijn Rutgers is supported by the Anna Foundation for Musculoskeletal Research in The Netherlands. Daniel BF Saris is supported by The Netherlands Organisation for Health Research and Development. Laura B Creemers is supported by the Dutch Arthritic Association (Reumafonds). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

executive summary

� Combined chondroitin sulfate in combination with glucosamine, hyaluronic acid or cyclooxygenase-2 inhibitors are the current treatment options available for osteoarthritis (OA); however, effectiveness is limited.

� Although promising for the future, current cytokine-modulating therapies for OA yield variable clinical results, and compelling in vivo mechanistic evidence is sparsely available.

� In OA synovial fluid, most cytokines, including IL-1b, are present at low levels whereas, after trauma, chondrodestructive as well as chondroprotective cytokines are present at increased levels.

� The increase in IL-6, IL-1b and TNF-a levels after trauma potentially provides a target for intra-articular intervention. The low chondrodestructive cytokine levels in OA synovial fluid may require a different approach for the OA joint.

� More knowledge on intra-articular processes and synovial fluid composition is required to optimize effectiveness of cytokine-modulating therapies for treatment of cartilage pathologies.



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� In addition to this specific review on the role of IL-1 and its receptor, earlier work by Arend is very constructive in explaining mechanisms of action of IL-1.

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Joint injury and osteoarthritis: soluble mediators in the course and treatment of cartilage...

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