Over the last years, the relevance of the matrix metalloproteinase (MMP) family in cancer research has grown considerably. These enzymes were initially associated with the invasive properties of tumour cells, owing to their ability to degrade all major protein components of the extracellular matrix (ECM) and basement membranes. However, further studies have demonstrated the implication of MMPs in early steps of tumour evolution, including stimulation of cell proliferation and modulation of angiogenesis. The establishment of causal relationships between MMP overproduction in tumour or stromal cells and cancer progression has prompted the development of clinical trials with a series of inhibitors designed to block the proteolytic activity of these enzymes. Unfortunately, the results derived from using broad-spectrum MMP inhibitors (MMPIs) for treating patients with advanced cancer have been disappointing in most cases. There are several putative explanations for the lack of success of these MMPIs including the recent finding that some MMPs may play a paradoxical protective role in tumour progression. These observations together with the identification of novel functions for MMPs in early stages of cancer have made necessary a reformulation of MMP inhibition strategies. A better understanding of the functional complexity of this proteolytic system and global approaches to identify the relevant MMPs which must be targeted in each individual cancer patient, will be necessary to clarify whether MMP inhibition may be part of future therapies against cancer.

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.

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.

Proteolytic events at the cell surface are essential in the regulation of signal transduction pathways. During the past years, the family of type II transmembrane serine proteases (TTSPs) has acquired an increasing relevance because of their privileged localization at the cell surface, although our current understanding of the biologic function of most TTSPs is limited. Here we show that matriptase-2 (Tmprss6), a recently described member of the TTSP family, is an essential regulator of iron homeostasis. Thus, Tmprss6 Ϫ/Ϫ mice display an overt phenotype of alopecia and a severe iron deficiency anemia. These hematologic alterations found in Tmprss6 Ϫ/Ϫ mice are accompanied by a marked up-regulation of hepcidin, a negative regulator of iron export into plasma. Likewise, Tmprss6 Ϫ/Ϫ mice have reduced ferroportin expression in the basolateral membrane of enterocytes and accumulate iron in these cells. Iron-dextran therapy rescues both alopecia and hematologic alterations of Tmprss6 Ϫ/Ϫ mice, providing causal evidence that the anemic phenotype of these mutant mice results from the blockade of intestinal iron export into plasma after dietary absorption. On the basis of these findings, we conclude that matriptase-2 activity represents a novel and relevant step in hepcidin regulation and iron homeostasis. IntroductionPericellular proteolysis is an essential event that determines the relations between the cell and its microenvironment. This crucial process in the development and maintenance of multicellular organisms requires the remodeling of extracellular matrix components as well as the posttranslational regulation of a wide range of cell-surface receptors, regulatory proteins, and adhesion molecules. 1 The increasing relevance of proteolytic processes localized at the cell surface has attracted notable attention on membraneassociated proteolytic systems, including the family of type II transmembrane serine proteases (TTSPs). 2,3 The TTSP family is composed of more than 20 different members that share a number of structural features: a single-pass transmembrane domain located near the short cytoplasmic amino-terminal tail, a central region containing different protein-interacting domains, and a carboxyterminal catalytic region with the structural characteristics of serine proteases. The large variability of the central modular region together with the diverse expression patterns of TTSP family members suggest that these enzymes may play different physiologic and pathologic roles, although only a few of these functions have been identified so far. Thus, enteropeptidase is mainly expressed in the duodenum and plays an essential role in food digestion as activator of pancreatic trypsinogen to trypsin. 4 Hepsin, is mainly expressed in liver, but it is highly up-regulated in prostate cancer. 5,6 Matriptase/MT-SP1 is a widely studied member of the TTSP family because of its relevance in diverse processes, including cancer progression. 7,8 Mutant mice deficient in matriptase die shortly after birth because of aberrant skin ...

Proteases are a set of enzymes that have been involved in multiple biological processes throughout evolution. Among them, extracellular matrix (ECM) remodeling has emerged as one of the most relevant functions exerted by these proteins, being essential in the regulation of critical events such as embryonic development or tissue homeostasis. Hence, it is not surprising that dysregulation in any protease function that affects ECM homeostasis may contribute to the aging process. Matrix metalloproteinases (MMPs) are one of the most important families of proteases involved in the tight control of ECM remodeling over time. In this review, we will discuss how MMPs and other proteases alter ECM composition and mechanical properties in aging, thereby affecting stem cell niches and the development of senescent phenotypes. Finally, we will summarize recent findings that associate MMPs with the development of age-related diseases, such as neurodegenerative disorders.