Osteoarthritis and its origins: Disease development at the cellular and molecular level - Veterinary Medicine
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Osteoarthritis and its origins: Disease development at the cellular and molecular level


Clinical Edge


Numerous studies in dogs and other species have documented increases in active MMPs, reductions in TIMP, or both, in osteoarthritis.9,11,12,14-22 For example, researchers demonstrated that the degree of cartilage degradation in knee osteoarthritis, as determined by arthroscopy, was strongly related to the activities of MMP-2 and MMP-13 and the reduced inhibitory effect of TIMP-2 on MMP-2.11

Synovial fluid from dogs with naturally occurring osteoarthritis and dogs with rheumatoid arthritis showed higher MMP-2 activity and dramatic increases in MMP-9 activity, compared with healthy controls.15,17 MMP-9 was correlated with rapidly destructive osteoarthritis in the hip joint of women undergoing total hip replacement.19 Similarly, MMP-3 and MMP-9 were increased in blood, and MMP-1, MMP-3, MMP-9, and TIMP-1 all were increased in tissue samples from patients with this severe form of osteoarthritis.20

An increase in MMP activity is stimulated by prostaglandins, including PGE2, which may be inhibited by nonsteroidal anti-inflammatory drugs or other compounds that decrease PGE2 production.23-26

Cytokines and inflammatory mediators

Cytokines represent a major class of signaling molecules involved in osteoarthritis. They include the catabolic proinflammatory cytokines and the anabolic anti-inflammatory cytokines. These cytokines not only regulate inflammatory events, but also regulate the expression of many of the previously mentioned MMPs and other factors.

IL-1 and TNF-α are the major catabolic cytokines involved in the destruction of articular cartilage. Both are produced by synovial cells and chondrocytes. IL-1 and TNF-α increase collagen type II degradation via MMPs, decrease the expression of TIMPs, and simultaneously inhibit extracellular matrix component expression.27-29 Both of these cytokines can elicit similar responses by themselves, but together the responses are more severe. In addition to cartilage degradation, these cytokines can stimulate the expression of inducible nitric oxide synthase and cyclooxygenase (COX)-2.30,31 This results in an abnormal accumulation of pro-oxidative nitric oxide and PGE2, increasing the inflammatory response and possibly suppressing cartilage synthesis.32


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