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.

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

Figure 1.

Zymography of the neutrophil gelatinase-associated lipocalin (NGAL)/matrix metalloproteinase 9 (MMP-9) complex from human neutrophils and the high molecular weight gelatinase activity recovered from osteoarthritis (OA) synovial fluid. Synovial fluid samples from three patients with OA (lanes 1–3) and the NGAL/MMP-9 complex purified from human neutrophils (lane 4) were analyzed by gelatin zymography. The migration positions of MMP-2, MMP-9 and the NGAL/MMP-9 complex are shown. Precision Plus Protein Standards (Bio-Rad, Hercules, CA) were employed as molecular size markers. (Reproduced with permission from Gupta et al. [2007].)

Figure 2.

Binding modalities of lipocalin. The ligand binding pocket of lipocalin is shown in (a) based on the structure of the lipocalin L1 binding pocket [Flower, 1996]. This schematic was originally drawn by Rebecca Sweet (University of Georgia, Athens, GA). The drawing shows that there are two types of binding modes that the lipocalins use to interact with soluble macromolecules. The binding modes are the covalent association type shown in (b) and the covalently-linked association type shown in (c) which is used by siderocalin.