Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo

•The matrix metalloproteinases (MMPs) are enzymes known for their remarkable ability to irreversibly degrade complex substrates in the extracellular matrix.•Despite their high structural homology at their catalytic domain, MMPs demonstrate indistinguishable substrate specificity in vitro.•In this review we provide a new perspective and fresh interpretation about MMP regulation in vivo.•We address the tight regulation of these enzymes at various levels, from gene expression to zymogen activation and endogenous inhibition and make a case for the selectivity of each MMP for its native substrates in vivo.•This intricate regulation is essential for maintaining tissue homeostasis, identifying the MMP regulatory factors at every level within each tissue will help develop new selective therapeutic agents against various diseases.

The matrix metalloproteinases (MMPs) play a crucial role in irreversible remodeling of the extracellular matrix (ECM) in normal homeostasis and pathological states. Accumulating data from various studies strongly suggest that MMPs are tightly regulated, starting from the level of gene expression all the way to zymogen activation and endogenous inhibition, with each level controlled by multiple factors. Recent in vivo findings indicate that cell–ECM and cell–cell interactions, as well as ECM bio-active products, contribute an additional layer of regulation at all levels, indicating that individual MMP expression and activity in vivo are highly coordinated and tissue specific processes.