Targeting Matrix Metalloproteinases in Inflammatory Conditions

Abstract

The matrix metalloproteinases (MMPs) and their endogenous regulators, the tissue inhibitors of MMPs (TIMPs) are responsible for the physiological remodelling of the extracellular matrix (ECM) in healthy connective tissues. MMPs are also involved in the regulation of cell behaviour via the release of growth factors and cytokines from the substrates they cleave, increasing the magnitude of their effects. Excess MMP activity is associated with ECM destruction in various inflammatory conditions, such as osteoarthritis (OA), while MMP under-activity potentially impairs healing by promoting fibrosis and preventing the effective removal of scar tissue. Both direct (TIMPs, small molecule MMP inhibitor drugs, blocking antibodies and anti-sense technologies) and indirect (glucocorticoids and non-steroidal anti-inflammatory drugs, statins, anti-sense technologies and various phytochemicals) strategies for MMP inhibition have been proposed and investigated. The strategy of MMP inhibition for degenerative and neoplastic diseases has been relatively unsuccessful due to undesired sequelae, often caused by non-selectivity of the MMP inhibition method. Therapeutic strategies for MMP-related conditions ideally should regulate MMP activity in order to maintain the optimum balance between MMPs and TIMPs. By avoiding complete inhibition it may be possible to prevent the complications of MMP over- and under-activity. Furthermore, MMP sub-type specificity is critical for minimising detrimental off-target effects that have been observed with broad-spectrum MMP inhibitors. Any potential MMP inhibitor or modulator must be subjected to rigorous pharmacokinetic, toxicity and safety studies and data obtained using in vitro models must be verified in clinically relevant animal models before therapeutic use is considered.

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

“…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. Further investigation revealed that prevention of cartilage vascularization (other than repression of MMPs) contributed to its anti-OA function.…”

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor

“…However, because the GSH skeleton is very difficult to work with due to its pharmacokinetic properties [5,10,11] , non-GSH analog inhibitors could potentially lead to an alternative approach that yields a successful drug. Furthermore, considering the potential off-target effects of metal chelation [20,21] , non-GSH analog GLOI inhibitors lacking Zn 2+ -coordination may be more suitable for lead optimization in drug development. The discoveries of indomethacin, zopolrestat and GA as GLOI inhibitors and their related complex crystal structures have demonstrated the existence of a novel non-GSH/non-Zn 2+ -chelation type of GLOI inhibitor with a carboxyl group as an essential anchor to fix the inhibitors in the active site by hydrogen bonding.…”

“…Docking and molecular dynamic simulation analyses also suggest that coordination with Zn 2+ is required for the inhibition of GLOI by curcumin, NSAIDs and flavonoids [10,18,19] . However, metal chelation is generally undesirable in drug development because of the high potential for off-target effects in the human body [20,21] . In our recent work, we determined the crystal structure of mouse glyoxalase I (mGLOI) complexed with indomethacin (inhibition constant (K i )=18 μmol/L, PDB ID: 4KYK) and zopolrestat (K i =1.2 μmol/L, PDB ID: 4KYH), revealing a novel inhibitor-GLOI binding mode [22] .…”

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

“…3). The matrix metalloproteinases (MMPs) comprise a family of 24 zinc-and calcium-dependent proteases that break down proteins of the extracellular matrix and basement membrane and modulate lung remodeling, fibrosis, and inflammation (157)(158)(159)(160)(161) The MMPs regulate important aspects of the immune response and are involved in chronic diseases such as arthritis, psoriasis, chronic obstructive pulmonary diseases, and cancer (162). MMPs can be categorized by the type of tissue degraded, including collagenases (MMP1), gelatinases (MMP9), stromelysins, and elastases.…”