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Meszaros E, Malemud CJ. Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Ther Adv Chronic Dis. 2012;3(5):219-29doi: 10.1177/2040622312454157.
Meszaros, E., & Malemud, C. J. (2012). Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Therapeutic advances in chronic disease, 3(5), 219-29. https://doi.org/10.1177/2040622312454157
Meszaros, Evan, and Malemud, Charles J. "Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity." Therapeutic advances in chronic disease vol. 3,5 (2012): 219-29. doi: https://doi.org/10.1177/2040622312454157
Meszaros E, Malemud CJ. Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Ther Adv Chronic Dis. 2012 Sep;3(5):219-29. doi: 10.1177/2040622312454157. PMID: 23342237; PMCID: PMC3539270.
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Ther Adv Chronic Dis. 2012 Sep;3(5):219-29. doi: 10.1177/2040622312454157.

Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity.

Therapeutic advances in chronic disease

Evan Meszaros, Charles J Malemud

Affiliations

  1. Division of Rheumatic Diseases, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

PMID: 23342237 PMCID: PMC3539270 DOI: 10.1177/2040622312454157

Abstract

Primary osteoarthritis (OA) is a musculoskeletal disorder of unknown etiology. OA is characterized by an imbalance between anabolism and catabolism in, and altered homeostasis of articular cartilage. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif are upregulated in OA joints. Extracellular matrix (ECM) proteins are critical for resistance to compressive forces and for maintaining the tensile properties of the tissue. Tissue inhibitor of metalloproteinases (TIMPs) is the endogenous inhibitor of MMPs, but in OA, TIMPs do not effectively neutralize MMP activity. Upregulation of MMP gene expression occurs in OA in a milieu of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor α. Presently, the medical therapy of OA includes mainly nonsteroidal anti-inflammatory drugs and corticosteroids which dampen pain and inflammation but appear to have little effect on restoring joint function. Experimental interventions to restore the imbalance between anabolism and catabolism include small molecule inhibitors of MMP subtypes or inhibitors of the interaction between IL-1 and its receptor. Although these agents have some positive effects on reducing MMP subtype activity they have little efficacy at the clinical level. MMP-9 is one MMP subtype implicated in the degradation of articular cartilage ECM proteins. MMP-9 was found in OA synovial fluid as a complex with neutrophil gelatinase-associated lipocalin (NGAL) which protected MMP-9 from autodegradation. Suppressing NGAL synthesis or promoting NGAL degradation may result in reducing the activity of MMP-9. We also propose initiating a search for enzyme-protein interactions to dampen other MMP subtype activity which could suppress ECM protein breakdown.

Keywords: gelatinase; matrix metalloproteinase; neutrophil gelatinase-associated lipocalin; osteoarthritis

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