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

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.

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

“…However, the MMP inhibitory capacity of TIMPs appears to be low in OA cartilage. 38 In addition, attempts to inhibit the overproduction of MMP subtypes in OA joints by employing exogenous Timps had little clinical efficacy. 39 Interestingly, Timp2 deletion mice resulted in OA-like phenotypes.…”

Cytokine, catabolic enzyme and structural matrix gene expression in synovial fluid following intra‐articular administration of triamcinolone acetonide in exercised horses

“…Articular cartilage destruction associated with osteoarthritis occurs as result of an imbalance between catabolic and anabolic processes [39]. Destruction of the cartilage occurs when catabolic processes predominate and is characterised by significant upregulation of MMPs [39].…”

Chitosan oligosaccharides inhibit IL-1β-induced chondrocyte apoptosis via the P38 MAPK signaling pathway

“…MMPs are a large group of enzymes responsible for tissue remodeling and cartilage disruption in arthritic joints because of their ability to degrade various ECM components [34,35]. An imbalance between MMPs and TIMPs is an determinant of the extent of ECM turnover [36]. Increasing evidence suggests a role for P38 MAPK in the regulation of protein synthesis by MMP-13 and TIMP-1 signaling.…”