[Frontiers in Bioscience 4, d694-703, October 15, 1999]

Current Issue

Received: 8/24/99
Accepted: 8/31/99

Send correspondence to:

Johanne Martel-Pelletier, Ph.D.,
Osteoarthritis Research Unit,
CHUM Hôpital Notre-Dame,
1560 rue Sherbrooke est,
Montréal, Québec, Canada H2L4M1

Tel.:514-281-6000 ext. 6658,
Fax: 514-896-4680,
E-mail: jmartelpelletier@


OA, Proinflammatory Cytokines, Antiinflammatory Cytokines, Cytokine Antagonists, Nitric Oxide, Review


Copyright © Frontiers in Bioscience, 1995


Johanne Martel-Pelletier1 , Nada Alaaeddine 2, Jean-Pierre Pelletier 3

1 University of Montréal, Director - Osteoarthritis Research Unit, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada, 2 University of Montréal, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada, 3 University of Montréal, Head - Rheumatic Disease Unit, Director - Osteoarthritis Research Unit, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada


1. Abstract

2. Introduction

3. Cytokines and osteoarthritis
3.1. Proinflammatory cytokines
3.2. Nitric oxide (NO): a catabolic factor
3.3. Antiinflammatory cytokines and cytokine antagonist
4. Future therapeutic approaches
5. Perspective
6. Acknowledgments
7. References

The specific causative agent of the pathological process of osteoarthritis (OA) has not yet been identified, however, episodic inflammation at the clinical stage is now a well documented phenomenon and believed to be involved in the disease progression. Interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are the predominant proinflammatory cytokines synthesized during the OA process. Other cytokines having proinflammatory properties or catabolic factors could also contribute to this pathological condition, and those having antiinflammatory properties may be able to counteract the negative effects of the former on the disease process. In this chapter, we will review cytokine interactions and their modulatory effects on joint articular tissue metabolism, including their stimulatory and/or inhibitory actions, and their potential relevance to OA. We will also briefly survey the major biological factors, in relation to cytokines, that look promising for future therapeutic approaches.


Osteoarthritis (OA), the most prevalent disorder of the musculoskeletal system, is believed to be a consequence of mechanical and biological events that destabilize the normal coupling of degradation and synthesis within articular joint tissues. The disease process affects not only the articular cartilage, but also the entire joint structure including the subchondral bone, ligaments, capsule, synovial membrane and periarticular muscles. Typical radiological changes in OA include joint space narrowing, subchondral bone sclerosis, and cyst and osteophyte formation. Clinical features also include joint pain, tenderness, limitation of movement, crepitus, occasional effusion and variable degrees of inflammation.

OA is generally classified as idiopathic (primary) or secondary, according to the presence or absence of certain factors. Secondary OA frequently develops in joints with preexisting structural abnormalities or absence of etiological factors. In primary OA, no trauma or other predisposing factor is identified, and intrinsic alterations of the articular tissue, or response to normal cumulative stresses, are presumed responsible (1).

A series of biomedical and inflammatory phenomena and etiological agents describes the etiopathogenesis of OA. This disease process involves a disturbance in the normal balance of degradation and repair in articular cartilage, synovial membrane and subchondral bone. Once cartilage degradation has begun, the synovial membrane phagocytoses the breakdown products released into the synovial fluid. Consequently, the membrane becomes hypertrophic and hyperplasic. Several studies have reported inflammatory changes in the synovial membrane of patients with OA that, on occasion, were almost indistinguishable from those in patients with an inflammatory arthritis such as rheumatoid arthritis (RA) (2-5).


It is believed that cytokines and growth factors play an important role in the pathophysiology of OA. They are closely associated with functional alterations in synovium, cartilage and subchondral bone, and are produced both spontaneously and following stimulation by the joint tissue cells. Cytokines and growth factors appear to be first produced by the synovial membrane, and diffused into the cartilage through the synovial fluid. They activate the chondrocytes, which in turn could produce catabolic factors such as proteases and proinflammatory cytokines. In OA synovial membrane, the synovial lining cells are key inflammatory effectors.

The major cytokines-(pro- and antiinflammatory) and antagonist - believed to be involved in OA pathophysiology include IL-1alpha, IL-1beta, IL-4, IL-6, IL-8, IL-10, IL-11, IL-13, IL-17, LIF, TNF-alpha as well as IL-1Ra. Several growth factors also appear to be involved in this disease, for example TGF-beta, FGF, PDGF and IGF. Some growth factors, such as TGF-beta, have a dual effect (synthetic or catabolic) that is dependent on the target cell, tissular location and concentration.

3.1. Proinflammatory cytokines

Proinflammatory cytokines are believed to play a pivotal role in the initiation and development of this disease process, among which IL-1beta and TNF-alpha appear prominent. IL-1beta is extremely important to cartilage destruction, while TNF-alpha appears to drive the inflammatory process (6-8). IL-1 and TNF-alpha can induce joint articular cells, such as chondrocytes and synovial cells, to produce other cytokines such as IL-8, IL-6, LIF and their own production, as well as stimulate proteases and prostaglandin E2 (PGE2) production. IL-1beta and TNF-alpha have also been shown to increase osteoclastic bone resorption in vitro (9). On the one hand, it has been demonstrated using cultured synovial fibroblasts that blocking IL-1 activity with the IL-1 receptor antagonist (IL-1Ra) reduced IL-6 and IL-8 production, but not that of TNF-alpha (10). On the other hand, adding anti-TNF-alpha antibodies to synovial cells greatly reduced the production of other proinflammatory cytokines such as IL-1, GM-CSF, IL-6 (11).

IL-1beta is primarily synthesized as a 31 kilodalton (kD) precursor, pro-IL-1beta devoid of a conventional signal sequence, and released in the active form of 17.5 kD (12,13). In articular joint tissue, including synovial membrane, synovial fluid and cartilage, IL-1beta has been found in the active form, and ex vivo experiments have demonstrated the ability of the OA synovial membrane to secrete this cytokine (14). Several serine proteases can process the pro-IL-1beta to bioactive forms (15) but in mammals only one protease, belonging to the cysteine-dependent protease family and named IL-1beta converting enzyme (ICE or Caspase-1), can specifically generate the mature 17.5 kD cytokine (15,16). ICE is a pro-enzyme polypeptide of 45 kD [p45] (15,16) located in the plasma membrane, and belonging to the family of cysteine aspartate-specific proteases known as caspases. Active ICE is produced following proteolytic cleavage of the pro-enzyme p45, generating two subunits known as p10 and p20, both of which are essential for enzymatic activity (17).

The biological activation of cells by IL-1 is mediated through association with specific cell-surface receptors (IL-1R). Two have been identified and named type I and type II (18). In articular tissue cells, the type I receptor, which has a slightly higher affinity for IL-1beta than for IL-1alpha, appears responsible for signal transduction (19-21). Type II IL-1R has a greater affinity for IL-1alpha than IL-1beta. It is unclear whether the type II receptor can mediate IL-1 cell signaling or if it serves to competitively inhibit IL-1 binding to type I IL-1R. The number of type I IL-1R is significantly increased in OA chondrocytes and synovial fibroblasts (20.,21). This appears to be responsible for the higher sensitivity of these cells to stimulation by IL-1 (20), a process that increases proteolytic enzyme gene upregulation, which in turn enhances cartilage destruction.

Both types of IL-1R can also be shed from the cell surface, and exist extracellularly in truncated forms; they are named IL-1 soluble receptors (IL-1sR). The shed receptor may function as a receptor antagonist because the ligand binding region is preserved, thus enabling it to compete with the membrane-associated receptors of the target cells. Similarly, the shedding of surface receptors may decrease the responsiveness of target cells to the ligand. It is suggested that type II IL-1R serves as the main precursor for shed soluble receptors. The binding affinity of IL-1sR to both IL-1 isoforms and IL-1Ra differs. Type II IL-1sR binds IL-1beta more readily than IL-1Ra; in contrast, type I IL-1sR binds IL-1Ra with high affinity (19,22,23). Therefore, when IL-1Ra and type I IL-1sR are both present their individual inhibitory effects are abrogated; however, when type II IL-1sR and IL-1Ra are combined, the resulting effect appears extremely beneficial, showing an additive effect.

In OA, TNF-alpha also appears to be an important mediator of matrix degradation and a pivotal cytokine in synovial membrane inflammation, although this cytokine is detected in OA articular tissue at a low level. TNF-alpha is synthesized as a precursor protein with amino-terminal extensions that are cleaved from the mature sequence prior to secretion. The prosequence of human TNF-alpha comprises 76 amino acids, and proteolytic cleavage takes place at the cellular surface. This cleavage appears to occur via a TNF-alpha converting enzyme named TACE belonging to a subfamily of the adamalysin (24). This enzyme is also required for shedding the TNF receptors. An upregulation of TACE mRNA in human OA cartilage has recently been reported (25). Following cleavage, the 233-residue prohormone of human TNF-alpha is converted to the 157-residue (17kD) secreted protein which oligomerizes to form trimers (26). The shape resembles a triangular cone with three subunits arranged edge to face.

TNF-alpha acts by binding to two specific receptors on the cell membrane. TNF-R are expressed on most tissues and in most cell lines with the exception of red blood cells, resting lymphocytes and a number of transformed B cells (27-29). These two TNF-R have apparent molecular masses of 55 to 60 kD and 75 to 80 kD (30.,31), and are named according to their molecular weight; TNF-R55 and TNF-R75. Their extracellular domains share 28% identity. This homology is also shared with other cell surface proteins, including the nerve growth factor receptor, Fas antigen, Bp 50, Ox 40 and CD27 (32,33). Interestingly, there is a complete absence of homology between the intracellular domains of the two TNF-R and any other known protein receptor (30,31,34,35). In articular tissue cells, TNF-R55 seems to be the dominant receptor responsible for mediating TNF-alpha activity. In OA chondrocytes and synovial fibroblasts, enhanced expression of TNF-R55 has been reported (36,37).

TNF-alpha induces multiple biological activities, and several distinct mechanisms of signal transduction may explain this diversity of action. First, although it is accepted that TNF-R55 is biologically relevant for several cell types, both receptor types appear to be actively involved in signal transduction (36,38-41). Indeed, in a given cell such as lymphocytes, each receptor type has been shown to induce a specific subset of TNF-alpha activities (42,43). It is suggested that the membrane receptors TNF-R55 and TNF-R75 are linked to distinct intracellular second-messengers. Second, it has been reported that TNF-R75 may regulate the rate of TNF-alpha association to TNF-R55 (44). TNF-R75/TNF-alpha complex may exhibit enhanced and/or specific intracellular function. Third, heterogeneity in the TNF-alpha response may also be caused by different postreceptor signal transduction pathways (45). Finally, TNF-alpha is a nondisulfide-bonded trimer that induces receptor trimerization by binding to its receptors. Each subunit makes contact with two adjacent receptor molecules, thus stabilizing the receptor trimer. It is not clear, however, if 1) receptor trimerization is necessary for activation, or 2) whether receptor dimerization is sufficient, or 3) if receptor trimerization triggers other and/or additional intracellular pathways.

Adding to the complexity of this cytokine, proteolytic cleavage of the extracellular domain of each TNF-R produces TNF-alpha soluble receptors (TNF-sR). The two soluble receptors, TNF-sR55 and TNF-sR75, are produced spontaneously by OA synovial fibroblasts and chondrocytes (36,46). These pathological cells have been found to release a significantly elevated level of the TNF-sR75 (36,46). TNF-sR are also found in the fluid of patients with different forms of arthritis, in quantities that vary according to disease status, with a higher ratio of TNF-sR75/TNF-sR55 noted in the more severe cases (47-49). It has been suggested, although not yet proven, that the biological role of the TNF-sR depends on its concentration in the joints. Thus, at low concentrations, TNF-sR stabilize the trimeric structure of TNF-alpha, thereby increasing the half-life of bioactive TNF-alpha (50), while at high concentrations, TNF-sR reduce the bioactivity of TNF-alpha by competing for TNF binding with cell-associated receptors (51). However, as the affinity of both TNF-sR is similar to that of the plasma membrane receptor, large amounts of these inhibitors are required to decrease TNF-alpha activity. To address this issue in vivo, chimeric proteins were generated between TNF-sR and Ig G domains (52). These fusion proteins were used in animal models and have been shown to display a high affinity. They have also been proven useful in the experimental therapy of septic shock, listeriosis and collagen arthritis (53-56).

The balance between cytokine-driven anabolic and catabolic processes determines the integrity of articular joint tissue. As previously mentioned, not all negative catabolic activity in OA articular tissue can be attributed to IL-1beta and TNF-alpha; other cytokines may also be involved. A shift in the balance between pro- and antiinflammatory cytokines is believed to contribute to the destructive processes in OA. Other proinflammatory cytokines including IL-8, LIF, IL-11, IL-6 and IL-17 have been shown to be expressed in OA tissue, and have therefore been considered potential contributing factors in the pathogenesis of this disease.

Interleukin-8 is a potent chemotactic cytokine for polymorphonuclear neutrophils (PMN), stimulating their chemotaxis and generating reactive oxygen metabolites (57). This chemokine is synthesized by a variety of cells including monocytes/macrophages, chondrocytes and fibroblasts (58-61). TNF-alpha can stimulate the release of IL-8 by these cells (61), and it is possible that IL-8 plays an important role in the acute inflammatory reaction. In synovial culture, TNF-alpha has been shown to stimulate the production of IL-8 in a time- and dose-dependent manner (61). In OA patients, IL-beta, IL-6, TNF-alpha and IL-8 coexist in the synovial fluid. IL-8 can enhance the release of inflammatory cytokines in human mononuclear cells, including that of IL-1beta, IL-6 and TNF-a , which may further modulate the inflammatory reaction (57). Deleuran et al (62) reported that the strongest expression of IL-8, in both OA and RA patients, was detected in the blood vessels and lining cell layers of the resected synovial membrane. The presence of IL-8 in the lining cell layers may well result in delivery to the synovial fluid, and could explain the high amount of IL-8 in this location. IL-8 is also present in the chondrocytes, and has been shown to enhance the production of oxidative and 5-lipoxygenase products (63). Lotz et al (64) have shown that human articular chondrocytes, stimulated by certain agents generated during response to cartilage injury (i.e.TNF-alpha), express the IL-8 gene and secrete bioactive IL-8.

Leukemia inhibitory factor (LIF) is a single-chain glycoprotein that has diverse effects, including induction of acute-phase protein synthesis and the inhibition of lipoprotein lipase activity. The LIF receptor is comprised of a combination of at least two chains: gp 130 (common to the IL-6 and IL-11 receptors) and gp 190 (65). A higher LIF level has been detected in synovial fluid of OA patients (66). LIF has been shown to enhance IL-1beta and IL-8 expression in chondrocytes, and IL-1beta and TNF-alpha in synovial fibroblasts (67). On various cell types, including those from articular joint tissue, IL-1beta and TNF-alpha upregulate LIF production (68-72). LIF regulates the metabolism of connective tissue such as cartilage and bone, and induces both the resorption and the formation of bone (73,74). LIF can induce expression of collagenase and stromelysin by human articular chondrocytes without affecting the production of the specific tissue inhibitor of metalloproteases, TIMP (69). This cytokine stimulates cartilage proteoglycan resorption (75) as well as nitric oxide (NO) production. These observations support the hypothesis that LIF may be directly and/or indirectly involved in the development of cartilage destruction and joint inflammation.

The IL-11 receptor shares the gp 130 domain with the LIF and IL-6 receptors, suggesting that they may have similar actions. This cytokine was originally identified as a stromal cell-derived lymphoietic and hematopoietic factor, but can also be induced in articular chondrocyte and synovial fibroblast cultures (76,77). IL-11 can be regulated on the transcriptional as well as the translational levels by various cytokines and growth factors (77). In addition, in articular chondrocytes and synovial fibroblasts, IL-11 does not increase the production of stromelysin, but is capable of inducing de novo synthesis of TIMP (77). Moreover, IL-11 has been found to decrease the release of PGE2 from OA synovial fibroblasts (78), suggesting that, contrary to the action of LIF, IL-11 can prevent the excessive extracellular matrix degeneration induced by synovial inflammation.

IL-6 has also been proposed as a contributor to the OA pathological process by: 1)increasing the number of inflammatory cells in synovial tissue (79); 2) stimulating the proliferation of chondrocytes; and 3) inducing an amplification of the IL-1 effects on the increased synthesis of metalloproteases (MMP) and inhibiting proteoglycan production (80). However, as IL-6 can induce the production of TIMP (81), and not MMP, it is believed that this cytokine is involved in the feedback mechanism that limits proteolytic damage.

IL-17 is a newly discovered cytokine of 20-30 kD present as a homodimer with variable glycosylated polypeptides (82). The tissue distribution of IL-17R appears ubiquitous, and it is not yet known whether all cells expressing IL-17R respond to its ligand. IL-17 upregulates a number of gene products involved in cell activation, including the proinflammatory cytokines IL-1beta, TNF-alpha and IL-6, as well as MMP in target cells such as human macrophages (83). IL-17 also increases the production of NO in chondrocyte cultures (84,85).

3.2. Nitric oxide (NO): a catabolic factor

It has also been proposed that the inorganic free radical NO is a potential factor in the promotion of cartilage catabolism in OA. Compared with the normal state, OA cartilage produces a large amount of NO, both under spontaneous and proinflammatory cytokine-stimulated conditions (86). A high level of nitrite/nitrate has been found in the synovial fluid and serum of arthritis patients (87,88). This is caused by an increased level of the inducible form of NO synthase (iNOS), the enzyme responsible for NO production (88,89). A chondrocyte-specific iNOS cDNA has been cloned and sequenced, and encodes a protein of 131 kD (90). The deduced amino acid sequence exhibits about 50% identity and 70% similarity to endothelial and neuronal forms of iNOS.

NO inhibits the synthesis of cartilage matrix macromolecules and enhances MMP activity (91,92). Moreover, elevated NO reduces the synthesis of IL-1Ra by chondrocytes (86). As such, an increased level of IL-1, in conjunction with a decreased IL-1Ra-level, may cause an over-stimulation of OA chondrocytes by this factor, leading to enhanced cartilage matrix degradation. Interestingly, a selective inhibitor of iNOS administered in vivo proved to exert positive therapeutic effects on the progression of lesions in an experimental canine OA model (93).

3.3. Antiinflammatory cytokines and cytokine antagonist

OA is characterized by progressive cartilage degradation, in which matrix integrity is no longer maintained and the homeostasis of catabolic cytokines (i.e.IL-1beta, TNF-alpha), anabolic cytokines (i.e. IGF, TGF-beta) and antiinflammatory cytokines or antagonist (i.e. IL-4, IL-10, IL-13 and IL-1Ra) is disturbed. Three antiinflammatory cytokines (IL-4, IL-10, IL-13) have been shown to be spontaneously elaborated by synovial membrane and cartilage, and are found in increased levels in the synovial fluid of OA patients. The antiinflammatory properties of these cytokines include decreased production of IL-1beta, TNF-alpha and MMP, upregulation of IL-1Ra and TIMP-1, and inhibition of PGE2 release (94-101). Although these cytokines share biological activities, their effects depend on the target cell of interest. For example, it was found that IL-10 modulated TNF-alpha production by increasing the release of the TNF-sR from monocytes in culture, while downregulating the receptor surface expression (99). In human OA synovial fibroblasts, IL-10 also downregulated the TNF-R density, while increasing the release of TNF-alpha-induced TNF-Rs75. In these cells, however, IL-4 upregulated TNF-R, and enhanced TNF-alpha-induced TNF-sR75 (101). This concurs with data from mononuclear cells from RA synovial fluid, in that both TNF-R55 and TNF-R75 were upregulated by IL-4 (102), and contrasts with findings from monocytes where this antiinflammatory cytokine downregulated both the membrane and soluble TNF-R (103). IL-13 inhibits lipopolysaccharide (LPS)-induced TNF-alpha production by mononuclear cells from peripheral blood and OA synovial fibroblasts, but not in cells recovered from the synovial fluid of OA and RA patients (104). In addition, the TNF receptor system does not appear to be a target for IL-13 in OA synovial fibroblasts (101).

Although only recently discovered, IL-13 has been shown to have important biological activities such as inhibiting the production of a wide range of proinflammatory cytokines in monocytes/macrophages, B cells, natural killer cells and endothelial cells, while increasing IL-1Ra production (104,105). In human synovial membrane specimens from OA patients treated with LPS, in vitro IL-13 inhibited the synthesis of IL-1beta, TNF-alpha and stromelysin, and increased production of IL-1Ra (100).

IL-1Ra is a competitive inhibitor of IL-1R. This molecule does not bind to IL-1, is not a binding protein, nor does it stimulate target cells. IL-1Ra can block many of the effects observed during the pathological process of OA, including PGE2 synthesis in synovial cells, collagenase production by chondrocytes, and cartilage matrix degradation. Three forms of IL-1Ra were found, one extracellular and termed soluble IL-1Ra (IL-1sRa), and two intracellular, icIL-1RaI and icIL-1RaII (19). Both the soluble and icIL-1Ra can bind to IL-1R, but with about 5-fold less affinity for the latter. Although intensive research is underway, the biological actions of icIL-1Ra remain elusive. In vitro experiments have revealed that an excess of 10-100 times the amount of IL-1Ra is necessary to inhibit IL-1beta activity whereas, in vivo, 100-2000 times more IL-1Ra is needed (14,19). This may likely explain why, even though a higher level of IL-1Ra is found in OA articular tissue, there is a relative deficit of IL-1Ra to IL-1beta in this tissue. This in turn may cause the increased level of IL-1beta activity.


A novel and interesting approach to controlling proinflammatory cytokine production and/or activity is the use of biological molecules possessing antiinflammatory properties. As such, recombinant human IL-4 (rhIL-4) has been tested in vitro on OA synovial tissue, and has been shown to suppress the synthesis of both IL-1beta and TNF-alpha in the same manner as low-dose dexamethasone (106). To date, of the antiinflammatory cytokines, only IL-10 is employed in clinical trials for the treatment of RA in humans. Results from IL-13 experimentation on human synovial membrane from OA patients (100) indicate it is potentially useful in the treatment of this disease. The capacity of IL-1Ra to reduce in vitro and in vivo cartilage degradation, MMP production and the progression of OA lesions (6,107) has elicited much attention concerning the use of this molecule in OA therapy, and more particularly in regard to gene therapy. Using the MFG retrovirus, the IL-1Ra gene has been successfully transferred into animal and human synovial cells using an ex vivo technique (108,109). One such study using the experimental dog model of OA showed in vivo that the progression of structural changes of OA was significantly reduced (107). It has also been demonstrated in vitro that the human IL-1Ra gene can be successfully transferred into chondrocytes using the Ad.RSV adenovirus, and that the resulting increase in production of IL-1Ra can protect the OA cartilage explants from degradation induced by IL-1 (109).

Although it is reasonable to focus therapeutic research on events responsible for initiating the catabolism cascade, benefits may also be realized by interrupting the general inflammatory process. One example of a potentially beneficial intervention would be to inhibit the activity of NO. Indeed, and as mentioned previously, findings regarding the action of NO on the biological functions of joint tissue suggest that controlling the production of this factor would have a potentially therapeutic value in OA. A recent study examining the in vivo effect of a selective inhibitor of iNOS on the progression of experimental OA showed that under prophylactic conditions, such an agent could reduce the progression of early lesions. In addition, the inhibition of NO production, correlated with a reduction of MMP activity in cartilage (93), was also associated with a reduced level of proinflammatory mediators (i.e.IL-1beta, PGE2 and NO) in the synovial fluid, and a marked reduction in the volume of joint effusion (93).


Although the primary etiology of OA remains undetermined, it is now believed that cartilage integrity is maintained by a balance obtained from cytokine-driven anabolic and catabolic processes. An excess of proinflammatory cytokines is thought to be responsible for many clinical manifestations of OA. Studies examining the contribution of cytokines to the pathogenesis of arthritic disease, including OA, have focused mainly on two proinflammatory cytokines, IL-1beta and TNF-alpha. In OA, the specific causative for the pathological process has not been identified, but synovial inflammation at the clinical stage is now a well-documented phenomenon. Other cytokines having inflammatory properties could contribute to this pathological process; therefore, these cytokines may represent a therapeutic way to prevent the consequences of inflammation in OA.

The therapeutic agents currently available to treat OA do not appear to block the major catabolic pathways; consequently, different cytokine-related therapies are being considered. Elucidating the mechanisms of action/interaction of ambient cytokines (both pro- and antiinflammatory) in OA articular joint tissue cells may provide the future foundation for targeting critical pathways through which drugs will be able to effectively block the proinflammatory action. This control may directly and/or indirectly decrease the release of degradative factors and inhibit the sequelae of the pathological process. Trends indicate a move toward the employment of antiinflammatory molecules. This change in philosophy is largely a result of the increasing interaction between basic and clinical research, which has been instrumental in specifically identifying the catabolic pathways, as well as providing opportunities to define new therapeutic approaches.

Despite the explosive growth of knowledge, our understanding as to how the individual proinflammatory cytokine players are regulated and orchestrated remains incomplete. Determining the regulation of proinflammatory cytokine activity is therefore critical to understanding articular joint degeneration. Progress in identifying the diverse pathogenic factors will eventually lead to more selective targets, superseding the current treatments for OA.


The authors thank Colleen Byrne and Shirley McCarthy for their secretarial assistance in manuscript preparation.


1. A.J. Hough: Pathology of osteoarthritis. In: arthritis and allied conditions. Ed: Koopman WJ, Williams and Wilkins, Baltimore, 1945-68 (1997)

2. S.L. Myers, K.D. Brandt, J.W. Ehlich, E.M. Braunstein, K.D. Shelbourne, D.A. Heck, L.A. Kalasinski: Synovial inflammation in patients with early osteoarthritis of the knee. J Rheumatol 17, 1662-9 (1990)

3. B. Haraoui, J.P. Pelletier, J.M. Cloutier, M.P. Faure, J. Martel-Pelletier: Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis. In vivo effects of anti-rheumatic drugs. Arthritis Rheum 34, 153-63 (1991)

4. S. Lindblad, E. Hedfors: Arthroscopic and immunohistologic characterization of knee joint synovitis in osteoarthritis. Arthritis Rheum 30, 1081-8 (1987)

5. M.N. Farahat, G. Yanni, R. Poston, G.S. Panayi: Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 52, 870-5 (1993)

6. J.P. Caron, J.C. Fernandes, J. Martel-Pelletier, G. Tardif, F. Mineau, C. Geng, J.P. Pelletier: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression. Arthritis Rheum 39, 1535-44 (1996)

7. F.A.J. Van de Loo, L.A. Joosten, P.L. van Lent, O.J. Arntz, W.B. van den Berg: Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 38, 164-72 (1995)

8. D. Plows, L. Probert, S. Georgopoulos, L. Alexopoulou, G. Kollias: The role of tumour necrosis factor (TNF) in arthritis: studies in transgenic mice. Rheumatol Eur Suppl 2, 51-4 (1995)

9. D.R. Bertolini, G.E. Nedwin, T.S. Bringman, D.D. Smith, G.R. Mundy: Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319, 516-8 (1986)

10. M. Feldmann, F.M. Brennan, R.N. Maini: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14, 397-440 (1996)

11. F.M. Brennan, D. Chantry, A. Jackson, R.N. Maini, M. Feldmann: Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244-7 (1989)

12. B. Mosley, D.L. Urdal, K.S. Prickett, A. Larsen, D. Cosman, P.J. Conlon, S. Gillis, S.K. Dower: The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem 262, 2941-4 (1987)

13. W.M. Siders, J.C. Klimovitz, S.B. Mizel: Characterization of the structural requirements and cell type specificity of IL-1a and IL-1b secretion. J Biol Chem 268, 22170-4 (1993)

14. J.P. Pelletier, R. McCollum, J.M. Cloutier, J. Martel-Pelletier: Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. J Rheumatol 22, 109-14 (1995)

15. R.A. Black, S.R. Kronheim, M. Cantrell, M.C. Deeley, C.J. March, K.S. Prickett, J. Wignall, P.J. Conlon, D. Cosman, T.P. Hopp, D.Y. Mochizuki: Generation of biologically active interleukin-1 beta by proteolytic cleavage of the inactive precursor. J Biol Chem 263, 9437-42 (1988)

16. S.R. Kronheim, A. Mumma, T. Greenstreet, P.J. Glackin, K. Van Ness, C.J. March, R.A. Black: Purification of interleukin-1 beta converting enzyme, the protease that cleaves the interleukin-1 beta precursor. Arch Biochem Biophys 296, 698-703 (1992)

17. K.P. Wilson, J.A. Black, J.A. Thomson, E.E. Kim, J.P. Griffith, M.A. Navia, M.A. Murcko, S.P. Chambers, R.A. Aldape, S.A. Raybuck: Structure and mechanism of interleukin-1 beta converting enzyme. Nature 370, 270-5 (1994)

18. J. Slack, C.J. McMahan, S. Waugh, K. Schooley, M.K. Spriggs, J.E. Sims, S.K. Dower: Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors. J Biol Chem 268, 2513-24 (1993)

19. W.P. Arend: Interleukin-1 receptor antagonist. [Review]. Adv Immunol 54, 167-227 (1993)

20. J. Martel-Pelletier, R. McCollum, J.A. Di Battista, M.P. Faure, J.A. Chin, S. Fournier, M. Sarfati, J.P. Pelletier: The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function. Arthritis Rheum 35, 530-40 (1992)

21. M. Sadouk, J.P. Pelletier, G. Tardif, K. Kiansa, J.M. Cloutier, J. Martel-Pelletier: Human synovial fibroblasts coexpress interleukin-1 receptor type I and type II mRNA: The increased level of the interleukin-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor. Lab Invest 73, 347-55 (1995)

22. C.A. Dinarello: Biologic basis for interleukin-1 in disease. Blood 87, 2095-147 (1996)

23. M. Svenson, M.B. Hansen, P. Heegaard, K. Abell, K. Bendtzen: Specific binding of interleukin-1(IL-1)-b and IL-1 receptor antagonist (IL-1ra) to human serum. High-affinity binding of IL-1ra to soluble IL-1 receptor type I. Cytokine 5, 427-35 (1993)

24. R.A. Black, C.T. Rauch, C.J. Kozlosky, J.J. Peschon, J.L. Slack, M.F. Wolfson, B.J. Castner, K.L. Stocking, P. Reddy, S. Srinivasan, N. Nelson, N. Boiani, K.A. Schooley, M. Gerhart, R. Davis, J.N. Fitzner, R.S. Johnson, R.J. Paxton, C.J. March, D.P. Cerretti: A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729-33 (1997)

25. A.R. Amin: Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting enzyme in human osteoarthritis. Osteoarthritis Cart 7, 392-4 (1999)

26. B.B. Aggarwal, W.J. Kohr, P.E. Hass, B. Moffat, S.A. Spencer, W.J. Henzel, T.S. Bringman, G.E. Nedwin, D.V. Goeddel, R.N. Harkins: Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem 260, 2345-54 (1985)

27. M.R. Shalaby, M.A.Jr. Palladino, S.E. Hirabayashi, T.E. Eessalu, G.D. Lewis, H.M. Shepard, B.B. Aggarwal: Receptor binding and activation of polymorphonuclear neutrophils by tumor necrosis factor-alpha. J Leukoc Biol 41, 196-204 (1987)

28. P. Scheurich, B. Thoma, U. Ucer, K. Pfizenmaier: Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol 138, 1786-90 (1987)

29. W. Digel, W. Schoniger, M. Stefanic, H. Janssen, C. Buck, M. Schmid, A. Raghavachar, F. Porzsolt: Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo. Blood 76, 1607-13 (1990)

30. H. Loetscher, Y.C.E. Pan, H.W. Lahm, R. Gentz, M. Brockhaus, H. Tabuchi, W. Lesslauer: Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell 61, 351-9 (1990)

31. T.J. Schall, M. Lewis, K.J. Koller, A. Lee, G.C. Rice, G.H. Wong, T. Gatanaga, G.A. Granger, R. Lentz, H. Raab: Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 61, 361-70 (1990)

32. N. Itoh, S. Yonehara, A. Ishii, M. Yonehara, S. Mizushima, M. Sameshima, A. Hase, Y. Seto, S. Nagata: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233-43 (1991)

33. D. Camerini, G. Walz, W.A. Loenen, J. Borst, B. Seed: The T cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family. J Immunol 147, 3165-9 (1991)

34. C.A. Smith, T. Davis, D. Anderson, L. Solam, M.P. Beckmann, R. Jerzy, S.K. Dower, D. Cosman, R.G. Goodwin: A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248, 1019-23 (1990)

35. M. Lewis, L.A. Tartaglia, A. Lee, G.L. Bennett, G.C. Rice, G.H. Wong, E.Y. Chen, D.V. Goeddel: Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci USA 88, 2830-4 (1991)

36. N. Alaaeddine, J.A. Di Battista, J.P. Pelletier, J.M. Cloutier, K. Kiansa, M. Dupuis, J. Martel-Pelletier: Osteoarthritic synovial fibroblasts possess an increased level of tumor necrosis factor-receptor 55 (TNF-R55) that mediates biological activation by TNF-alpha. J Rheumatol 24, 1985-94 (1997)

37. C.I. Westacott, R.M. Atkins, P.A. Dieppe, C.J. Elson: Tumour necrosis factor-alpha receptor expression on chondrocytes isolated from human articular cartilage. J Rheumatol 21, 1710-5 (1994)

38. M.R. Shalaby, A. Sundan, H. Loetscher, M. Brockhaus, W. Lesslauer, T. Espevik: Binding and regulation of cellular functions by monoclonal antibodies against human tumor necrosis factor receptors. J Exp Med 172, 1517-20 (1990)

39. B. Naume, R. Shalaby, W. Lesslauer, T. Espevik: Involvement of the 55- and 75-kDa tumor necrosis factor receptors in the generation of lymphokine-activated killer cell activity and proliferation of natural killer cells. J Immunol 146, 3045-8 (1991)

40. H.P. Hohmann, M. Brockhaus, P.A. Baeuerle, R. Remy, R. Kolbeck, A.P. van Loon: Expression of the types A and B tumor necrosis factor (TNF) receptors is independently regulated, and both receptors mediate activation of the transcription factor NF-kappa B. TNF alpha is not needed for induction of a biological effect via TNF receptors. J Biol Chem 265, 22409-17 (1990)

41. B. Thoma, M. Grell, K. Pfizenmaier, P. Scheurich: Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med 172, 1019-23 (1990)

42. L.A. Tartaglia, R.F. Weber, I.S. Figari, C. Reynolds, M.A.Jr. Palladino, D.V. Goeddel: The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci USA 88, 9292-6 (1991)

43. O.M. Howard, K.A. Clouse, C. Smith, R.G. Goodwin, W.L. Farrar: Soluble tumor necrosis factor receptor: inhibition of human immunodeficiency virus activation. Proc Natl Acad Sci USA 90, 2335-9 (1993)

44. L.A. Tartaglia, D. Pennica, D.V. Goeddel: Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J Biol Chem 268, 18542-8 (1993)

45. S. Schutze, K. Potthoff, T. Machleidt, D. Berkovic, K. Wiegmann, M. Kronke: TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown. Cell 71, 765-76 (1992)

46. F.M. Brennan, D.L. Gibbons, A.P. Cope, P. Katsikis, R.N. Maini, M. Feldmann: TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immunol 42, 158-65 (1995)

47. I.C. Chikanza, P. Roux-Lombard, J.M. Dayer, G.S. Panayi: Tumour necrosis factor soluble receptors behave as acute phase reactants following surgery in patients with rheumatoid arthritis, chronic osteomyelitis and osteoarthritis. Clin Exp Immunol 92, 19-22 (1993)

48. P. Roux-Lombard, L. Punzi, F. Hasler, S. Bas, S. Todesco, H. Gallati, P.A. Guerne, J.M. Dayer: Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum 36, 485-9 (1993)

49. A.P. Cope, D. Aderka, M. Doherty, H. Engelmann, D. Gibbons, A.C. Jones, F.M. Brennan, R.N. Maini, D. Wallach, M. Feldmann: Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum 35, 1160-9 (1992)

50. D. Aderka, H. Engelmann, Y. Maor, C. Brakebusch, D. Wallach: Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 175, 323-9 (1992)

51. M. Higuchi, B.B. Aggarwal: Inhibition of ligand binding and antiproliferative effects of tumor necrosis factor and lymphotoxin by soluble forms of recombinant P60 and P80 receptors. Biochem Biophys Res Commun 182, 638-43 (1992)

52. K. Peppel, D. Crawford, B. Beutler: A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J Exp Med 174, 1483-9 (1991)

53. A. Kalinkovich, H. Engelmann, N. Harpaz, R. Burstein, V. Barak, I. Kalickman, D. Wallach, Z. Bentwich: Elevated serum levels of soluble tumour necrosis factor receptors (sTNF-R) in patients with HIV infection. Clin Exp Immunol 89, 351-5 (1992)

54. A. Ythier, M.P. Gascon, P. Juillard, C. Vesin, D. Wallach, G.E. Grau: Protective effect of natural TNF-binding protein on human TNF-induced toxicity in mice. Cytokine 5, 459-62 (1993)

55. M. Haak-Frendscho, S.A. Marsters, J. Mordenti, S. Brady, N.A. Gillett, S.A. Chen, A. Ashkenazai: Inhibition of TNF by a TNF receptor immunoadhesin. Comparison to an anti-TNF monoclonal antibody. J Immunol 152, 1347-53 (1994)

56. L.W. Moreland, P.W. Pratt, R.P. Bucy, B.S. Jackson, J.W. Feldman, W.J. Koopman: Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term followup of CD4+ T cell counts. Arthritis Rheum 37, 834-8 (1994)

57. C.L. Yu, K.H. Sun, S.C. Shei, C.Y. Tsai, S.T. Tsai, J.C. Wang, T.S. Liao, W.M. Lin, H.L. Chen, H.S. Yu, S.H. Han: Interleukin 8 modulates interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha release from normal human mononuclear cells. Immunopharmacology 27, 207-14 (1994)

58. J. Van Damme, R.A. Bunning, R. Conings, R. Graham, G. Russell, G. Opdenakker: Characterization of granulocyte chemotactic activity from human cytokine-stimulated chondrocytes as interleukin 8. Cytokine 2, 106-11 (1990)

59. A.E. Koch, S.L. Kunkel, J.C. Burrows, H.L. Evanoff, G.K. Haines, R.M. Pope, R.M. Strieter: Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 147, 2187-95 (1991)

60. M.S. Kristensen, K. Paludan, C.G. Larsen, C.O. Zachariae, B.W. Deleuran, P.K. Jensen, P. Jorgensen, K. Thestrup-Pedersen: Quantitative determination of IL-1 alpha-induced IL-8 mRNA levels in cultured human keratinocytes, dermal fibroblasts, endothelial cells, and monocytes. J Invest Dermatol 97, 506-10 (1991)

61. K. Hirota, T. Akahoshi, H. Endo, H. Kondo, S. Kashiwazaki: Production of interleukin 8 by cultured synovial cells in response to interleukin 1 and tumor necrosis factor. Rheumatol Int 12, 13-6 (1992)

62. B. Deleuran, P. Lemche, M.S. Kristensen, C.Q. Chu, M. Field, J. Jensen, K. Matsushima, K. Stengaard-Pedersen: Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol 23, 2-7 (1994)

63. J.M. Schroder: The monocyte-derived neutrophil activating peptide (NAP/interleukin 8) stimulates human neutrophil arachidonate-5-lipoxygenase, but not the release of cellular arachidonate. J Exp Med 170, 847-63 (1989)

64. M. Lotz, R. Terkeltaub, P.M. Villiger: Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. J Immunol 148, 466-73 (1992)

65. T. Kishimoto, T. Taga, S. Akira: Cytokine signal transduction. Cell 76, 253-62 (1994)

66. J. Dechanet, J.L. Taupin, P. Chomarat, M.C. Rissoan, J.F. Moreau, J. Banchereau, P. Miossec: Interleukin-4 but not interleukin-10 inhibits the production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes. Eur J Immunol 24, 3222-8 (1994)

67. P.M. Villiger, Y. Geng, M. Lotz: Induction of cytokine expression by leukemia inhibitory factor. J Clin Invest 91, 1575-81 (1993)

68. Y. Ishimi, E. Abe, C.H. Jin, C. Miyaura, M.H. Hong, M. Oshida, H. Kurosawa, Y. Yamaguchi, M. Tomida, M. Hozumi: Leukemia inhibitory factor/differentiation-stimulating factor (LIF/D- factor): regulation of its production and possible roles in bone metabolism. J Cell Physiol 152, 71-8 (1992)

69. M. Lotz, T. Moats, P.M. Villiger: Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 90, 888-96 (1992)

70. I.K. Campbell, P. Waring, U. Novak, J.A. Hamilton: Production of leukemia inhibitory factor by human articular chondrocytes and cartilage in response to interleukin-1 and tumor necrosis factor alpha. Arthritis Rheum 36, 790-4 (1993)

71. J.A. Hamilton, P.M. Waring, E.L. Filonzi: Induction of leukemia inhibitory factor in human synovial fibroblasts by IL-1 and tumor necrosis factor-alpha. J Immunol 150, 1496-502 (1993)

72. J.A. Lorenzo, S.L. Jastrzebski, J.F. Kalinowski, E. Downie, J.H. Korn: Tumor necrosis factor alpha stimulates production of leukemia inhibitory factor in human dermal fibroblast cultures. Clin Immunol Immunopathol 70, 260-5 (1994)

73. E. Abe, H. Tanaka, Y. Ishimi, C. Miyaura, T. Hayashi, H. Nagasawa, M. Tomida, Y. Yamaguchi, M. Hozumi, T. Suda: Differentiation-inducing factor purified from conditioned medium of mitogen-treated spleen cell cultures stimulates bone resorption. Proc Natl Acad Sci USA 83, 5958-62 (1986)

74. L.R. Reid, C. Lowe, J. Cornish, S.J. Skinner, D.J. Hilton, T.A. Willson, D.P. Gearing, T.J. Martin: Leukemia inhibitory factor: a novel bone-active cytokine. Endocrinology 126, 1416-20 (1990)

75. G.J. Carroll, M.C. Bell: Leukaemia inhibitory factor stimulates proteoglycan resorption in porcine articular cartilage. Rheumatol Int 13, 5-8 (1993)

76. S.R. Paul, F. Bennett, J.A. Calvetti, K. Kelleher, C.R. Wood, R.M. O'Hara Jr., A.C. Leary, B. Sibley, S.C. Clark, D.A. Williams: Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci USA 87, 7512-6 (1990)

77. R. Maier, V. Ganu, M. Lotz: Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases. J Biol Chem 268, 21527-32 (1993)

78. N. Alaaeddine, J.A Di Battista, J.P. Pelletier, K. Kiansa, J.M. Cloutier, J. Martel-Pelletier: Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE2 release and on signalling pathways in human OA synovial fibroblasts. Cytokine, in press (1999)

79. P.A. Guerne, B.L. Zuraw, J.H. Vaughan, D.A. Carson, M. Lotz: Synovium as a source as interleukin-6 in vitro: Contribution to local and systemic manifestations of arthritis. J Clin Invest 83, 585-92 (1989)

80. J.J. Nietfeld, B. Wilbrink, M. Helle, J.L. van Roy, W. den Otter, A.J. Swaak, O. Huber-Bruning: Interleukin-1-induced interleukin-6 is required for the inhibition of proteoglycan synthesis by interleukin-1 in human articular cartilage. Arthritis Rheum 33, 1695-701 (1990)

81. M. Lotz, P.A. Guerne: Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity. J Biol Chem 266, 2017-20 (1991)

82. Z. Yao, S.L. Painter, W.C. Fanslow, D. Ulrich, B.M. Macduff, M.K. Spriggs, R.J. Armitage: Human IL-17: a novel cytokine derived from T cells. J Immunol 155, 5483-6 (1995)

83. D. Jovanovic, J.A. Di Battista, J. Martel-Pelletier, F.C. Jolicoeur, Y. He, M. Zhang, F. Mineau, J.P. Pelletier: Interleukin-17 (IL-17) stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160, 3513-21 (1998)

84. M.G. Attur, R.N. Patel, S.B. Abramson, A.R. Amin: Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage. Arthritis Rheum 40, 1050-3 (1997)

85. J. Martel-Pelletier, F. Mineau, D. Jovanovic, J.A. Di Battista, J.P. Pelletier: MAPK and NF-kB together regulate the IL-17-induced nitric oxide production in human OA chondrocytes: possible role of transactivating factor MAPKAP-K. Arthritis Rheum (in press) (1999)

86. J.P. Pelletier, F. Mineau, P. Ranger, G. Tardif, J. Martel-Pelletier: The increased synthesis of inducible nitric oxide inhibits IL-1Ra synthesis by human articular chondrocytes: possible role in osteoarthritic cartilage degradation. Osteoarthritis Cart 4, 77-84 (1996)

87. A.J. Farrell, D.R. Blake, R.M. Palmer, S. Moncada: Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51, 1219-22 (1992)

88. I.B. McInnes, B.P. Leung, M. Field, X.Q. Wei, F.P. Huang, R.D. Sturrock, A. Kinninmonth, J. Weidner, R. Mumford, F.Y. Liew: Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J Exp Med 184, 1519-24 (1996)

89. P.S. Grabowski, P.K. Wright, R.J. Van't Hof, M.H. Helfrich, H. Ohshima, S.H. Ralston: Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid arthritis and osteoarthritis. Br J Rheumatol 36, 651-5 (1997)

90. I.G. Charles, R.M. Palmer, M.S. Hickery, M.T. Bayliss, A.P. Chubb, V.S. Hall, D.W. Moss, S. Moncada: Cloning, characterization and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci USA 90, 11419-23 (1993)

91. D. Taskiran, M. Stefanovic-Racic, H.I. Georgescu, C.H. Evans: Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun 200, 142-8 (1994)

92. G.A.C. Murrell, D. Jang, R.J. Williams: Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 206, 15-21 (1995)

93. J.P. Pelletier, D. Jovanovic, J.C. Fernandes, P.T. Manning, J.R. Connor, M.G. Currie, J.A. Di Battista, J. Martel-Pelletier: Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum 41, 1275-86 (1998)

94. P.H. Hart, G.F. Vitti, D.R. Burgess, G.A. Whitty, D.S. Piccoli, J.A. Hamilton: Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci USA 86, 3803-7 (1989)

95. R. Essner, K. Rhoades, W.H. McBride, D.L. Morton, J.S. Economou: IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol 142, 3857-61 (1989)

96. M. Shingu, S. Miyauchi, Y. Nagai, C. Yasutake, K. Horie: The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. Br J Rheumatol 34, 101-6 (1995)

97. R.P. Donnelly, M.J. Fenton, D.S. Finbloom, T.L. Gerrard: Differential regulation of IL-1 production in human monocytes by IFN-gamma and IL-4. J Immunol 145, 569-75 (1990)

98. E. Vannier, L.C. Miller, C.A. Dinarello: Coordinated antiinflammatory effects of interleukin 4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proc Natl Acad Sci USA 89, 4076-80 (1992)

99. P.H. Hart, M.J. Ahern, M.D. Smith, J.J. Finlay-Jones: Comparison of the suppressive effects of interleukin-10 and interleukin- 4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Immunology 84, 536-42 (1995)

100. D. Jovanovic, J.P. Pelletier, N. Alaaeddine, F. Mineau, C. Geng, P. Ranger, J. Martel-Pelletier: Effect of IL-13 on cytokines, cytokine receptors and inhibitors on human osteoarthritic synovium and synovial fibroblasts. Osteoarthritis Cart 6, 40-9 (1998)

101. N. Alaaeddine, J.A. Di Battista, J.P. Pelletier, K. Kiansa, J.M. Cloutier, J. Martel-Pelletier: Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways. Arthritis Rheum 42, 710-8 (1999)

102. A.P. Cope, D.L. Gibbons, D. Aderka, B.M. Foxwell, D. Wallach, R.N. Maini, M. Feldmann, F.M. Brennan: Differential regulation of tumour necrosis factor receptors (TNF-R) by IL-4; upregulation of P55 and P75 TNF-R on synovial joint mononuclear cells. Cytokine 5, 205-12 (1993)

103. D.A. Joyce, D.P. Gibbons, P. Green, J.H. Steer, M. Feldmann, F.M. Brennan: Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes. Eur J Immunol 24, 2699-705 (1994)

104. R. de Waal Malefyt, C.G. Figdor, R. Huijbens, S. Mohan-Peterson, B. Bennett, J.A. Culpepper, W. Dang, G. Zurawski, J.E. de Vries: Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol 151, 6370-81 (1993)

105. T. Defrance, P. Carayon, G. Billian, J.-C. Guillemot, A. Minty, D. Caput, P. Ferrara: Interleukin 13 is a B cell stimulating factor. J Exp Med 179, 135-43 (1994)

106. A. Bendrups, A. Hilton, A. Meager, J.A. Hamilton: Reduction of tumor necrosis factor alpha and interleukin-1 beta levels in human synovial tissue by interleukin-4 and glucocorticoid. Rheumatol Int 12, 217-20 (1993)

107. J.P. Pelletier, J.P. Caron, C.H. Evans, P.D. Robbins, H.I. Georgescu, D. Jovanovic, J.C. Fernandes, J. Martel-Pelletier: In vivo suppression of early experimental osteoarthritis by IL-Ra using gene therapy. Arthritis Rheum 40, 1012-9 (1997)

108. C.H. Evans, P.D. Robbins: Gene therapy for arthritis. In: Gene therapeutics: methods and applications of direct gene transfer. Ed: Wolff JA, Birkhauser, Boston, 320-43 (1994)

109. V.M. Baragi, R.R. Renkiewicz, H. Jordan, J. Bonadio, J.W. Harman, B.J. Roessler: Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest 96, 2454-60 (1995)