Therapeutic developments in matrix metalloproteinase inhibition

Abstract

A family of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs) have the capacity to degrade all elements of the extracellular matrix (ECM) and are required for homeostatic maintenance of the ECM. However, interest in MMPs predominantly arises from the accumulating evidence implicating that dysregulated MMP expression plays a role in mediating or accompanying a diverse array of pathologies. These include tumour invasion and metastasis and inflammatory diseases characterised by excessive tissue destruction, such as arthritis, periodontal disease, atherosclerosis, plaque rupture, arterial aneurysms, postmyocardial infarction, ventricular remodelling and cardiac rupture. Several patents representing therapeutic drugs and strategies to treat the associated conditions have been claimed, some resulting in clinical drug trials. This review will: i) summarise the current status of our understanding of MMPs and how they participate in normal and functional ECM degradation; ii) review therapeutic efforts to favourably alter the balance between MMP proteolysis and ECM sythesis; and iii) critically evaluate recent studies that have importantly advanced our understanding of the complexities of MMP function and propose areas where future efforts to develop therapeutic strategies might be most beneficial and productive.

• arthritis
• atherosclerosis
• cancer
• extracellular matrix (ECM)
• inflammation
• matrix metalloproteinase (MMP)
• membrane type-matrix metalloproteinase (MT-MMP)
• metastasis
• plaque rupture
• pro-MMP
• proprotein convertases
• protease
• protease inhibition
• tissue inhibitor of matrix metalloproteinase (TIMP)
• tissue remodelling