From Blunt to Sharp Scissors in Health and Disease

Our view of the matrix metalloproteinases (MMPs) has expanded considerably in recent years. More than four decades ago, Gross and Lapiere described a collagenolytic activity involved in tail resorption in tadpoles and initiated the MMP era. At the beginning, most studies in this field analyzed the ability of these enzymes to degrade extracellular matrix and basement membrane protein components in both normal and pathological conditions. The proposal that MMPs would be essential for peritumor tissue degradation and cancer dissemination, represented a guiding paradigm in the study of these proteinases and stimulated multiple efforts aimed at developing MMP inhibitors (MMPIs) as anticancer agents. Likewise, the association of MMPs with other common pathological processes such as arthritis, neurological alterations or cardiovascular diseases further stimulated the incorporation of new research groups to the MMP field and the proliferation of studies on the structure, function and regulation of these enzymes. However, despite the promising role of MMPs as therapeutic targets in virtually all major human pathological conditions, the first clinical trials with MMPIs yielded disappointing results. This situation initially dampened interest and enthusiasm for MMPs but fortunately, it opened the door to a new and brilliant time in the MMP field: the post-trial era.

The first consequence of the re-evaluation of the role of MMPs in the context of human biology and pathology has been the recognition of the large complexity of this family of proteolytic enzymes. At the time that the initial MMPI clinical trials were designed, only three MMPs had been discovered. Since then, the human genome sequence has allowed us to view the portraits of the entire MMP family: a group of more than 20 different components with a growing structural and functional complexity. Furthermore, large families of related metalloproteinases such as ADAMs and ADAMTSs have been described and their connections with MMPs have been established in some cases. The growing complexity of MMPs is also appreciated in the number and diversity of substrates that can be targeted by these enzymes. Thus, in addition to their classical connective tissue-remodeling functions, MMPs act as processing enzymes that perform highly selective and limited cleavage of specific substrates including growth factors and their receptors, cell adhesion molecules, cytokines, chemokines, apoptotic ligands and angiogenic factors. The recent characterization of new MMP substrates as well as the generation of genetically modified animal models of gain or loss of MMP function, have demonstrated the relevance of these enzymes in multiple processes from which life and death depend in all cellular societies. Thus, evidence has been accumulated on the participation of MMPs in cell proliferation, differentiation, adhesion and migration, or in processes such as angiogenesis, apoptosis, inflammation and immune defense. This impressive diversity in both substrates and functions of MMPs has provided some explanations for the paradoxical positive and negative effects of these enzymes in reproduction, development, wound healing and aging, or in pathological conditions such as cancer, arthritis, asthma, lung fibrosis, encephalomyelitis, and cardiovascular diseases. Therefore, an increased knowledge of the physiological functions of MMPs is clearly required in order to understand the complex roles of these multifunctional enzymes in human pathology and to design improved MMP-inhibition strategies for therapeutic intervention. The 2007 Gordon Research Conference on Matrix Metalloproteinases will cover these new aspects which arose after the changing view of these enzymes from blunt to sharp scissors in health and disease. For this purpose, in Il Ciocco (Italy), we will present the most recent and innovative unpublished research on MMPs, related proteinases and their inhibitors in a multidisciplinary manner, and in a friendly atmosphere including both academic and industrial scientists. The program will cover new mouse models of disease, in vivo imaging, degradomics, structural biology and mechanistic aspects related to the roles of MMPs in processes such as development, immunity, angiogenesis and cancer. We will conjugate the contributions of well-established MMP laboratories with those of researchers more recently incorporated to this field. Several short talks have been reserved for trainees that will be selected from the poster abstracts and a few full speaker slots have been held for the latest breaking works. We hope that the beautiful environment and additional activities possible in Tuscany will ensure an interactive, enthusiastic and fun meeting that features the most innovative metalloproteinase research of our time. Carl Blobel and I invite all MMP scientists to attend the GRC to be held at Il Ciocco, Tuscany, Italy, June 3-8, 2007.

Carlos Lopez-Otin, Chair
2007 GRC on "Matrix Metalloproteinases"