Matrix metalloproteinases: Evolution, gene regulation and functional analysis in mouse models

Abstract

Matrix metalloproteinases (MMPs) are a large family of zinc-endopeptidases which play important roles in multiple physiological and pathological processes. These enzymes are widely distributed in all kingdoms of life and have likely evolved from a single-domain protein which underwent successive rounds of duplication, gene fusion and exon shuffling events to generate the multidomain architecture and functional diversity currently exhibited by MMPs. Proper regulation of these enzymes is required to prevent their unwanted activity in a variety of disorders, including cancer, arthritis and cardiovascular diseases. Multiple hormones, cytokines and growth factors are able to induce MMP expression, although the tissue specificity of the diverse family members is mainly achieved by the combination of different transcriptional control mechanisms. The integration of multiple signaling pathways, coupled with the cooperation between several cis-regulatory elements found at the MMP promoters facilitates the strict spatiotemporal control of MMP transcriptional activity. Additionally, epigenetic mechanisms, such as DNA methylation or histone acetylation, may also contribute to MMP regulation. Likewise, post-transcriptional regulatory processes including mRNA stability, protein translational efficiency, and microRNA-based mechanisms have been recently described as modulators of MMP gene expression. Parallel studies have led to the identification of MMP polymorphisms and mutations causally implicated in the development of different genetic diseases. These genomic analyses have been further extended through the generation of animal models of gain- or loss-of-function for MMPs which have allowed the identification of novel functions for these enzymes and the establishment of causal relationships between MMP dysregulation and development of different human diseases. Further genomic studies of MMPs, including functional analysis of gene regulation and generation of novel animal models will help to answer the multiple questions still open in relation to a family of enzymes which strongly influence multiple events in life and disease.

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

“…Furthermore, MMPs including MMP-9 has been shown to exhibit an opposing role at different stages of disease progression including renal disease. [26][27][28] Overall, the above observations highlight the complex biological function of MMP-9 that has previously been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 in UUO model via MMP-9 inhibition.…”

A Novel Mechanism of Latency in Matrix Metalloproteinases

“…MMPs are found throughout animals and plants (9 -12), where their distribution is consistent with a Darwinian tree-based pathway. In addition, polyplication has led to several paralogous MMP genes being present in the same organism: 24 in humans, 26 in sea urchin, 26 in zebrafish, seven in sea squirt, and two in fruit fly (11). In contrast, only a patchy phylogenetic distribution of genes encoding hypothetical orthologs has been found in viruses, Bacteria, Archaea, and fungi.…”

“…In MMPs, the CSBZ encompasses three histidine zinc ligands, the general base/acid glutamate for catalysis, and a structurally relevant glycine (3). In addition, the distinct MMP paralogs are multidomain proteins that display a disparate domain organization that is the result of successive polyplication, gene fusion, and exon shuffling (11). The only domains common to all animal and plant MMPs are a signal peptide, which is removed after secretion, a prodomain and a catalytic domain, as found, e.g.…”

Pseudogenization of the tooth gene enamelysin (MMP20) in the common ancestor of extant baleen whales

“…MMP20 may also be necessary to activate kallikreinrelated peptidase 4 (KLK4; [29,30]), which cleaves and degrades remnants of enamel matrix proteins during the maturation stage of amelogenesis. MMP20-deficient mice have an amelogenesis imperfecta phenotype that is characterized by thin, hypomineralized enamel that easily chips away from the underlying dentin [31,32]. There are also mutations in the human MMP20 gene that cause non-syndromic amelogenesis imperfecta [30].…”