MMP inhibition and osteoarthritis

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

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Osteoarthritis (OA)is the most common form of arthritis.

In western countries, x-ray evidence of OA is present in the majority of persons by 65 years of age and in about 80 percent of persons more than 75 years of age. Approximately, 11 percent of persons more than 64 years of age have symptomatic osteoarthritis of the knee. (Data from the CDC, Atlanta)

The development of OA is a complex process involving genetic, biomechanical, and inflammatory factors.

Research has elucidated some of these mechanisms. The following are a few papers that present some of the information known about how OA develops.

Expert Reviews in Molecular Medicine: Accession information: (01)00320-9h.htm (shortcode: txt001arn); 5 July 2001

Cartilage catabolism in arthritis: factors that influence homeostasis

Andrew D. Rowan

OA falls into two categories: primary OA occurs in middle-aged to elderly patients where an active disease process is often presumed to be a consequence of joint ‘wear and tear’; secondary OA occurs at any age as a result of trauma or disease. In both situations, the central feature is loss of articular cartilage and a reduced capacity for repair; the chondrocytes themselves appear to be the driving force behind these deficiencies. A focal lesion in the cartilage might lead to abnormal loading of the surrounding chondrocytes, which, in turn, respond by promoting a cascade of slow but persistent degradation of cartilage, ultimately leading to loss of joint function. The cyclical disease course of OA has also been proposed to be the result of sequential cytokine stimulation followed by a feedback inhibition of autocrine cytokine and cytokine receptor production, which affects collagenase synthesis. Although not considered an inflammatory disease, orthopaedic surgeons often comment on the marked synovial infiltration seen during joint replacement surgery of OA patients, further increasing the evidence for the involvement of pro-inflammatory cytokines such as IL-1 and TNF-.

Degradation and synthesis of cartilage macromolecules under normal physiological conditions is kept in equilibrium and can therefore be viewed as a balance. Chondrocytes and synovial cells respond to a variety of cytokines and growth factors that stimulate the production of destructive proteinases. All four major classes of proteolytic enzymes (aspartic, cysteine, serine and metallo) are involved in normal turnover and pathological destruction, and the pathway that predominates will alter depending on the resorptive circumstances. These pathways are not mutually exclusive and it is highly probable that total degradation of matrix components involves several pathways and classes of proteinases.

MMPs are a family of neutral zinc endoproteinases that collectively degrade all the components of the ECM, and have received considerable attention with respect to arthritic tissue destruction because their expression correlates strongly with collagen degradation, although this is not always the case. The MMP family contains at least three collagenases [interstitial collagenase/collagenase 1 (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13)] that can degrade fibrillar collagen. MMPs are controlled at several levels, including inhibition by a family of endogenous inhibitors called the tissue inhibitors of metalloproteinases (TIMPs). MMP inhibition has been the subject of much research in recent years by the pharmaceutical industry in an attempt to find a highly potent, specific and bioavailable inhibitor. Other metalloproteinases, most notably of the ADAM (for ‘a disintegrin and metalloproteinase’) family of proteinases, are also expressed in cartilage, although their roles in tissue maintenance and tissue destruction are still unclear. In particular, a subset of this family known as the ADAMTS (ADAM with thrombospondin motifs) proteins contains members that have recently been found to specifically cleave aggrecan at the site considered to be pathologically relevant. At least one of these enzymes (ADAMTS-5) is also expressed in the synovium. Although these metalloproteinases are not MMPs, recent evidence indicates that TIMP-3 is a potent inhibitor.

Cysteine proteinases (cathepsins B and L, which can degrade cartilage and bone) are expressed in RA synovial lining, and have been implicated in cartilage degradation. Cathepsin K has received recent attention because it is now thought to be strongly associated with pathological bone and cartilage resorption. Serine proteinases, particularly those associated with the plasmin cascade, have also been implicated in tissue destruction.

The role of MMPs in the pathological destruction of cartilage is promoted by various pro-inflammatory cytokines that perturb the balance between synthesis and degradation of ECM components to favour matrix breakdown. Proteoglycan (i.e. aggrecan) loss is a rapid event following pro-inflammatory stimulation but it can be readily replaced once the stimulus is removed. Collagen is more resistant to degradation but is much more difficult to replace. However, a different situation arises during normal cartilage metabolism (the so-called physiological ‘steady-state’). Under these circumstances, degradation of collagen, and indeed probably proteoglycan, occurs within the lysosomal system following phagocytosis, a mechanism shown to occur in fibroblasts. Although phagocytosis has not been described in chondrocytes, CD44-mediated endocytosis and breakdown of hyaluronate has been reported, suggesting differences in mechanisms of ECM breakdown among mesenchymal cells. Nevertheless, an equilibrium exists whereby matrix turnover is tightly regulated; any disturbance of the various degradative pathways that prevail might lead to uncontrolled matrix destruction.

Biomechanical and biochemical forces are involved in cartilage destruction, which is at the core of osteoarthritis. Cytokines and growth factors are thought to play a role in the pathophysiology of the disorder. Interleukin-1 and tumor necrosis factor-b may function to activate enzymes involved in proteolytic digestion of cartilage. Growth factors such as tissue growth factor-b and insulin growth factor-1 may play a role in the body's attempts to repair cartilage through cartilage synthesis.

When catabolism exceeds cartilage synthesis, osteoarthritis develops. Collagenolytic enzymes are thought to contribute to the breakdown of cartilage. Collagenase 1 (matrix metalloproteinase-1 [MMP-1]) is a fibroblast collagenase, and collagenase 2 (MMP-8) is a neutrophil collagenase. Collagenase 3 (MMP-13) may be particularly important because of its highly potent collagenolytic activity.

Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor.

Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA.

Procter & Gamble Pharmaceuticals Inc., 8700 Mason-Montgomery Rd, Mason, OH 45040, USA.

OBJECTIVE: Characterize a model of osteoarthritis (OA) induced by a surgically transecting the medial collateral ligament and meniscus. Evaluate the effectiveness of a matrix metalloproteinase (MMP) inhibitor in this model. METHODS: The medial collateral ligament of the right knee of rats was transected and a single full thickness cut was made through meniscus. Rats were sacrificed at various times after the surgery to assess the severity of gross cartilage damage using an image analyser and microscopically by histology. The effect of an MMP inhibitor in this model was assessed by administering compound twice daily for the 21 days and evaluating gross and histological joint damage at day 21. The in vitro potency of the MMP inhibitor (MMPI) against a panel of human recombinant MMPs was assessed kinetically using a quenched fluorescent substrate. RESULTS: Surgical transection of the medial collateral ligament and meniscus resulted in a time dependent increase in the severity of the cartilage lesion (depth) as measured histologically but only a slight increase in the area of the lesion as assessed grossly by image analysis. Administration of a MMPI orally twice daily (b.i.d.) at 25mg/kg to rats in the meniscal tear model resulted in significant inhibition of cartilage degradation and osteophyte formation (total joint score) of 39+/-7% (mean+/-S.E.M., from four separate experiments). CONCLUSION: These results demonstrate that MMP inhibition is effective in reducing the joint damage that occurs in the meniscal tear model of OA and support a potential therapeutic role for MMP inhibition in the treatment of human OA. Copyright 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.

PMID: 12359164 [PubMed - indexed for MEDLINE] Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes.

Liacini A, Sylvester J, Li WQ, Zafarullah M.

Departement de Medecine and Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame du CHUM, 1560 Sherbrooke est, Montreal, Quebec, Canada H2L 4M1.

Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46-53% (MMP-3) and 59-66% (MMP-13) inhibition of RNA induction in human OA and 47-52% (MMP-3) and 69-73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37-77% (MMP-3) and 43-73% (MMP-13) suppression in human and 77-100% (MMP-3) and 96-100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35-37% reduction of MMP-3 and MMP-13 RNA in human and 36-46% (MMP-3) and 60-88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-kappa B, curcumin, achieved 48-99% suppression of MMP-3 and 45-97% of MMP-13 in human and 8-100% (MMP-3) and 32-100% (MMP-13) in bovine chondrocytes. NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54-64% for MMP-3 and 74-93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis.

PMID: 12009331 [PubMed - indexed for MEDLINE] Glucosamine Sulfate Inhibits Nitric Oxide and Stromelysin Production in Cartilage Cultures and Reverses IL–1 Inhibition of Osteoarthritic Articular Cartilage Synthesis I Yaron, I Shirazi, R Judovich, M Yaron

The primary enzymes responsible for the degradation of cartilage are the matrix metalloproteinases (MMPs). Under normal conditions, MMP synthesis, activation, and inhibition are tightly regulated at several levels. In OA, synthesis of MMPs is greatly enhanced, overwhelming the available inhibitors. Nitric oxide has been implicated as a possible mediator of osteoarthritis development and cartilage deterioration.

The purpose of this study was to elucidate the mechanism by which Glucosamine sulfate plays a role in managing OA in the knee. Cartilage from OA patients undergoing total knee replacement was cultured with and without IL–1 (1 ng/ml) or LPS (3 µg/ml) in the presence of Glucosamine sulfate (1, 10, and 100 µg/ml). Nitrous oxide (NO) and stromelysis (MMP–3) content in the culture media, as well as cartilage synthesis by 35S incorporation were measured.

There was a four–fold increase in nitrous oxide release present in both IL–1 and LPS cultures that was inhibited in a dose–dependent manner by Glucosamine sulfate, reaching statistical significance at a dose of 100 µg/ml, 60% and 38% (P<0.05), respectively. IL–1 and LPS stimulated MMP–3 production was also significantly (P<0.05) inhibited by Glucosamine sulfate at a dose of 100 µg/ml. The inhibition of cartilage synthesis by IL–1 (70%) and LPS (50%) cultures was reversed by the presence of Glucosamine sulfate, reaching statistical significance (P<0.05) at 10 µg/ml.

Glucosamine sulfate may minimize the damage to articulate cartilage in patients with OA by blocking the inhibition of cartilage synthesis by IL–1 and by inhibiting NO and MMP–3 production.

Bottom line: matrix metalloproteinases (MMPs)play a major role in cartilage degradation.

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