Uncoupling of inflammatory and destructive mechanisms in arthritis,☆☆

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Abstract

Objective: To update clinicians on recent advances in the differentiation of the mechanisms of inflammation and cartilage destruction in the pathogenesis of rheumatoid arthritis (RA). Methods: We present analysis of recent published literature and abstracts that elucidates the independent actions of pivotal proinflammatory cytokines. These experimental data provide the framework for understanding the uncoupling of destructive and inflammatory mechanisms in arthritis. Results: Tumor necrosis factor–alpha (TNF-α) is an important mediator in the inflammation that occurs in RA. Interleukin-1 (IL-1) has a dominant effect on cartilage destruction that occurs later in the disease process. TNF-independent IL-1 production occurs in many RA model situations. Cytokine balance determines the erosive nature of the disease. Conclusion: IL-1 is at least as important as TNF-α in promoting the disease process. The pathways by which the inflammatory and destructive changes occur suggest that targeted anticytokine intervention will arrest the cartilage damage that occurs in patients with RA. Semin Arthritis Rheum 30:7-16 (Suppl 2). Copyright © 2001 by W.B. Saunders Company

Section snippets

Mechanism of cartilage destruction

Inflamed synovial tissue releases enzymes, growth factors, and the major cytokines TNF-α and IL-1. The latter 2 mediators can then directly activate chondrocytes in the articular cartilage surface. Activation of chondrocytes leads to the release of destructive enzymes and an inhibition of matrix synthesis.

Figure 2 shows stages of inflammation and its impact on mouse articular cartilage.

. Articular cartilage proteoglycan loss in early arthritis, mouse model. (A) The arrows are proteoglycans on

TNF and IL-1 in animal models of arthritis

Several studies in animal models have been conducted to elucidate the distinct roles of TNF-α and IL-1 in the manifestations of RA; namely, inflammation and cartilage destruction (Table 1).

. Experimental Approaches to Elucidating the Roles of TNF and IL-1

Identify arthritogenic potency of recombinant cytokines
Effect of local overexpression of cytokines in joints
Development of TNF and IL-1 transgenic mice
Studies with neutralizing antibodies, soluble receptors, and IL-1Ra in a range of experimental

Enzyme involvement in cartilage damage

Kinetic analysis of neoepitope expression can provide insight into enzyme cascades involved in the destruction of cartilage seen in RA. Proteoglycan molecules are normally linked to hyaluronic acid molecules. If an enzyme (eg, aggrecanase, which cleaves at a major proteoglycan epitope) affects those molecules, the NITEGE neoepitope endings at the clipped proteoglycan would still link with hyaluronic acid and thus stay in the cartilage. The remnant of the cleaved proteoglycan will leave the

Balance of factors in cartilage destruction

The action of destructive cytokines in cartilage erosion is offset by modulatory cytokines and growth factors (Fig 9).

. Mechanisms of cartilage metabolism.

Destructive cytokines such as TNF-α, IL-1, and IL-17 have a major impact on chondrocytes in 2 ways: They inhibit synthesis and induce enzyme release. Balancing modulatory cytokines include IL-4, which up-regulates IL-1Ra and soluble receptors to counteract IL-1. These modulatory cytokines also have direct effects on the articular chondrocytes,

Summary

IL-1 is a much more potent mediator of destruction in the articular cartilage than TNF-α. In TNF-transgenic models, the destructive process can be blocked with antibodies to the IL-1 receptor (7). Although there were still high levels of TNF-α in those animals, TNF-α does not produce arthritis alone; it can only induce arthritis by inducing IL-1. TNF-independent IL-1 production has been shown in many different models; there is no erosive arthritis in IL-1β–deficient backgrounds. Finally, recent

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    Wim B. van den Berg, PhD: Professor of Experimental Rheumatology, Head of Rheumatology Research Laboratory, Department of Rheumatology and Advanced Therapeutics, University Medical Center, Nijmegen, the Netherlands.

    ☆☆

    Address reprint requests to Wim B. van den Berg, PhD, Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, 189, Geert Grooteplein Zuid 26-28, Nijmegen 6500 HB, the Netherlands.

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