Uncoupling of inflammatory and destructive mechanisms in arthritis☆,☆☆
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.
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).
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). 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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Low innate production of interleukin-1β and interleukin-6 is associated with the absence of osteoarthritis in old age
2010, Osteoarthritis and CartilageCitation Excerpt :Moreover, IL-1β and TNF-α have also been shown to induce osteoclastic bone resorption in vitro, a phenomenon that may be involved in the remodeling of OA subchondral bone5–7,9. Animal studies have confirmed the essential role of IL-1β in cartilage destructive processes28. The role of IL-6 is less clear.
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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.
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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.