Rheumatoid Arthritis: Buttle DJ

Dickinson SC, Vankemmelbeke MN, Buttle DJ, Rosenberg K, Heinegård D, Hollander AP. · Academic Rheumatology, University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, BS10 5NB, Bristol, UK. · Matrix Biol. · Pubmed #12853037 No free full text.

Abstract: Cartilage oligomeric matrix protein (COMP) is a pentameric glycoprotein present in cartilage, tendon and ligament. Fragments of the molecule are present in the diseased cartilage, synovial fluid and serum of patients with knee injuries, osteoarthritis and rheumatoid arthritis. Although COMP is a substrate for several matrix metalloproteinases (MMPs), the enzymes responsible for COMP degradation in vivo have yet to be identified. In this study we utilised well-established bovine cartilage culture models to examine IL-1alpha-stimulated COMP proteolysis in the presence and absence of MMP inhibitors. COMP was released from bovine nasal cartilage, in response to IL-1alpha, at an intermediate time between proteoglycans and type II collagen, when soluble MMP levels in the culture medium were undetectable. The major fragment of COMP released following IL-1alpha-stimulation migrated with an apparent molecular mass of approximately 110 kDa (Fragment-110) and co-migrated with both the major fragment present in human arthritic synovial fluid samples and the product of COMP cleavage by purified MMP-9. However, the broad-spectrum MMP and ADAM inhibitor BB94 only partially inhibited the formation of Fragment-110 and failed to inhibit COMP release significantly. Therefore the results of these studies indicate a role for proteinases other than MMPs in the degradation of COMP in bovine cartilage. It was further demonstrated that purified COMP was cleaved by ADAMTS-4, but not ADAMTS-1 or -5, to yield a fragment which co-migrated with Fragment-110. Therefore this is the first demonstration of COMP as a substrate for ADAMTS-4, although it remains to be determined whether this enzyme plays a role in COMP degradation in vivo.

Adcocks C, Collin P, Buttle DJ. · Division of Genomic Medicine, University of Sheffield Medical School, Sheffield S10 2RX, UK. · J Nutr. · Pubmed #11880552 links to  free full text

Abstract: Polyphenolic compounds from green tea have been shown to reduce inflammation in a murine model of inflammatory arthritis, but no studies have been undertaken to investigate whether these compounds are protective to joint tissues. We therefore investigated the effects of catechins found in green tea on cartilage extracellular matrix components using in vitro model systems. Bovine nasal and metacarpophalangeal cartilage as well as human nondiseased, osteoarthritic and rheumatoid cartilage were cultured with and without reagents known to accelerate cartilage matrix breakdown. Individual catechins were added to the cultures and the amount of released proteoglycan and type II collagen was measured by metachromatic assay and inhibition ELISA, respectively. Possible nonspecific or toxic effects of the catechins were assessed by lactate output and proteoglycan synthesis. Catechins, particularly those containing a gallate ester, were effective at micromolar concentrations at inhibiting proteoglycan and type II collagen breakdown. No toxic effects of the catechins were evident. We conclude that some green tea catechins are chondroprotective and that consumption of green tea may be prophylactic for arthritis and may benefit the arthritis patient by reducing inflammation and slowing cartilage breakdown. Further studies will be required to determine whether these compounds access the joint space in sufficient concentration and in a form capable of providing efficacy in vivo.

Vankemmelbeke MN, Holen I, Wilson AG, Ilic MZ, Handley CJ, Kelner GS, Clark M, Liu C, Maki RA, Burnett D, Buttle DJ. · Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK. · Eur J Biochem. · Pubmed #11231277 links to  free full text

Abstract: ADAMTS proteinases, belonging to the adamalysin subfamily of metalloproteinases, have been implicated in a variety of cellular events such as morphogenesis, cell migration, angiogenesis, ovulation and extracellular matrix breakdown. Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) have been identified in cartilage and are largely responsible for cartilage aggrecan breakdown. We have shown previously that synovium, the membrane lining diarthrodial joints, generates soluble aggrecanase activity. We report here the expression, localization and activity of ADAMTS-5 from human arthritic and bovine synovium. ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1 alpha or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage. Aggrecanase activity generated by synovium in vitro and recombinant ADAMTS-5 cleaved aggrecan extensively, resulting in aggrecan fragments similar to those generated by chondrocyte-derived aggrecanases, and the activity was inhibited by heparin. ADAMTS-5 was immunolocalized in human arthritic synovium, where staining was mostly pericellular, particularly in the synovial lining and around blood vessels; some matrix staining was also seen. The possibility that synovium-derived ADAMTS-5 may play a role in cartilage aggrecan breakdown is discussed.