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Matrix catabolism in arthritis: priming the guns with oncostatin M.

Cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL-1) have long been at the forefront as “guns” in inflammatory arthritis: they are effective in inducing destructive catabolic matrix metalloproteinase (MMP) release by resident connective tissue cells of the synovium, cartilage, and bone, and they are delivered by armies of immune and inflammatory cells that invade synovium and fluid of affected joint tissues1. More recent data also implicate IL-17 in mediating similar activation of catabolic mechanisms. Clearly, other cytokines may also participate in the pathophysiology of these tissues in vivo through different mechanisms, and we suggest that the macrophage/T cell/neutrophil product oncostatin M (OSM) is critical in priming connective tissue cells for robust responses to IL-1, TNF, and IL-17 in vitro and in vivo. Reduction in symptoms of pain and swelling of inflamed joints in rheumatoid arthritis (RA), although in large part controlled by nonsteroidal antiinflammatory drugs and/or steroid therapy, is not tightly coupled to control of the destruction of joint tissue. Inflammation of RA joints involves numerous sets of molecules (eicosanoids, adhesion molecules, cytokines and chemokines, RANK/RANKL among others); however, catabolism of cartilage and bone in joint disease is a prime end effect of both rheumatoid and osteoarthritic disease. The direct effectors of catabolism include activated enzymes, primarily of the MMP family (particularly MMP-1, MMP-13, and aggrecanase in joint tissues)2,3; moreover, mechanisms for generation and control involving endogenous inhibitors such as the family of TIMP (tissue inhibitor of MMP)4 have been the subject of extensive work over several years. Osteoarthritis may also involve IL-1 and TNF mediation of MMP and aggrecanase expression5,6. Where targeting immune T and B lymphocytes that initiate autoimmune mechanisms in RA has been difficult due to lack of specific methods, targeting acute inflammation symptoms and effector mechanisms of extracellular matrix catabolism has been and is currently a reasonable tack for treating established disease. The establishment of therapies devised to block TNF or IL-1 has been well documented in animal models of arthritis. These have been translated to the clinic, where TNF blockade therapy in particular, either antibodies to TNF or soluble TNF receptor moieties, has been established as effective7,8 in a proportion of patients. However the action of such regimens may not include consistent amelioration of joint destruction, let alone repair of affected cartilage, bone, and synovial tissue. Further, a subset of patients are not responsive at all. Lack of efficacy in patient subpopulations may be a result of relatively late administration of anticytokine therapy, since early subclinical rheumatoid or osteoarthritis is not easily identifiable at present. Certainly the relative success of TNF or IL-1 blockade therapy has instilled confidence in the success of targeting such molecules as an approach, and fuels further investigations of novel cytokine therapies and/or combination approaches. Targeting IL-1 and TNF in combination therapy would be predicted to be more effective than either alone9, since IL-1 blockade (IL-1 receptor antagonist) showed success in preclinical trials in animal models and some success in clinical trials. However, a recent limited clinical trial of TNF and IL-1 blockade did not show predicted increased efficacy and led to increased side effects (infection). Combination therapies for RA patients using TNF blockade and methotrexate (MTX) clearly have an advantage over either treatment alone10. Although the method(s) by which MTX acts in RA patients is still not clear, one assumes it is different than IL-1 or TNF blockade, since MTX does not show such properties in vitro. This supports the notion of increased efficacy of combination treatments that target different mechanisms of action. The control of chronic inflammation is unclear certainly in human disease, and studies have explored various angles in hematopoietic, immune, and effector function regulation. Elucidating the mechanisms of chronic inflammation awaits clarification of the interplay between various molecules, including cytokines and target cells, and evolution over the time course of disease development, including latter stages of destruction of the normal extracellular matrix of synovium, cartilage, and bone. The success of existing approaches in animal models may not reflect similar efficacy in human subjects due to differences between species in