We further discuss recent information on MMP mutant mouse models which shed light on the functional relevance of these enzymes to multiple physiological and pathological processes.Дue to their widespread substrate spectrum, MMPs are integrated as important regulators for tissue homeostasis and immunity in the network of multidirectional communication within tissues and cells. This review provides an overview of the basic biological functions of these endopeptidases, paying special attention to novel findings on their complex regulation and broad substrate spectrum which has been recently significantly expanded through high-throughput degradomic screens. ДЄlthough the activity of MMPs has been shown to be essential in cell biological processes and many fundamental physiological events involving tissue remodelling, such as angiogenesis, bone development, wound healing and mammary involution, the increasing interest in MMP function mainly stems from their role in several pathological conditions, such as cancer or chronic inflammatory diseases. In contrast, most of the other human MMP genes are located on different chromosomes, resulting in a total of 10 distinct chromosomes for all 24 human MMP genes.

The cluster in the human genome is located at chromosome 11q22 and contains MMP-1, -3, -7, -8, -10, -12, -13, -20 and -27. Taking this into account, some of the actual MMP members are most likely derivatives from a single gene resulting in a MMP gene cluster, whose organisation is preserved from amphibians to mammals. The diversity of the current mammalian MMP gene families is derived particularly from an extensive gene tandem duplication and exon shuffling during evolution in the tetrapod lineages. At least 25 different vertebrate MMPs have been characterised up to now and 24 different MMPs are found in humans, including the two identical forms for MMP-23, encoded by two distinct genes, i.e. High sequence similarity to MMP catalytic domains is found in almost all kingdoms of life. However recent substrate identification studies reveal that MMPs are regulating the release or activation of chemokines, cytokines, growth factors, antibiotic peptides, and other bioactive molecules thus participating in physiological processes such as innate and adaptive immunity, inflammation, angiogenesis, bone remodelling, and neurite growth. In the classical view, MMPs are collectively capable of degrading all components of the extracellular matrix (ECM) and basement membrane, restricting their functions to tissue remodelling and maintenance. The matrixins or matrix metalloproteinases (MMPs) are members of the large metzincin superfamily like the astacins, serralysins, reprolysins, and adamalysins or disintegrin metalloproteinases (ADAMs). Advancing our understanding of the MMP contribution to tissue homeostasis will lead us to identify causal relationships between their dysregulation and the development of disease pathologies, thus guiding us to successful MMP-directed therapies. Analysis of MMP mutant mice has proved to be an essential tool for the identification of novel functions and interactions of single MMP members. Dysregulated MMP activity leads to pathological conditions such as arthritis, inflammation and cancer, thus highlighting MMPs as promising therapeutic targets. MMP activity is tightly controlled at the level of transcription, pro-peptide activation and inhibition by tissue inhibitors of MMPs. Due to the broad spectrum of their substrate specificity, MMPs contribute to the homeostasis of many tissues and participate in several physiological processes, such as bone remodelling, angiogenesis, immunity and wound healing. It was originally thought that their main function is to degrade the various components of the extracellular matrix (ECM), yet recent studies have led us to appreciate their significance as regulators of extracellular tissue signalling networks. Matrix metalloproteinases (MMPs) are members of the metzincin group of proteases which share the conserved zinc-binding motif in their catalytic active site.

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