Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, ma-trix metalloproteinases are proteases capable of remodel-ing the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcrip-tional control, all of which are unrelated to the degrada-tion of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP re-search, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still mis-conceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimen-tal functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will dis-cuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future phar-macological alternatives to inhibit their detrimental functions in diseases.Significance Statement--Matrix metalloprotei-nases (MMPs) have been implicated in most inflamma-tory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progres-sion and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.