We are at the end of the beginning in understanding MMP biology…

Rather than being primarily involved in matrix degradation MMPs have equally or more important roles as efficient processing enzymes of many bioactive mediators such as cytokines, chemokines, growth factors, their receptors and specific matrix protein anchors for these molecules. Limited and specific processing of bioactive mediators can lead to profound alterations in cell behaviour resulting in shedding of cell surface molecules, activation and inactivation of signalling molecules-sometimes converting activity from agonists to antagonists, and for certain proteins, exposing cryptic biologically active epitopes and neoproteins from precursor extracellular molecules of unrelated function. These diverse and important functions potentially explain the paradoxical positive and negative effects of MMPs in cancer and the results of Phase III MMP inhibitor (MMPI) drug trials that, despite recent encouraging results showing that Marimastat has efficacy in the treatment of certain gastric carcinomas, have otherwise been largely disappointing. Hence, a dramatically increased understanding of the physiological functions of MMPs is clearly required in order to understand the roles of MMPs and TIMPs in pathology and to devise rational targeting strategies for therapeutic intervention with new generations of MMP inhibitors.

On this backdrop, the 2003 MMP Gordon Research Conference will present the most recent and innovative research in MMPs, related proteinases and their inhibitors in a multidisciplinary manner and in a new program format. Moreover, many new and establishing investigators have been invited to present their work alongside those from established laboratories. Several short talks are reserved for trainees that will be selected from the poster abstracts and a few full speaker slots have been held for the latest breaking stories. Together with the recreational activities possible at Big Sky, I hope this ensures a vibrant, interactive, enthusiastic and fun meeting that features the most innovative MMP research of our time.

In Montana 2003, the processing functions of MMPs will be emphasised with respect to interconnections of the MMP family with signalling networks that alter overall cell behaviour; in this regard the critical roles of the ADAMs in a large variety of cell surface shedding events will also be presented. The future outlook and potential for MMPIs in cancer therapy will be discussed throughout the meeting in relation to new discoveries on the positive and negative roles of MMPs in cancer. Mirroring the discovery that tetracyclines are MMPIs, the surprise morphing of British Biotech MMPIs into a new class of potent antibiotics that target the bacterial metalloenzyme peptide deformylase and which are now in Phase I trials will be presented as will the emerging roles of metalloproteinases in infection. The importance of MMPs in physiological turnover of collagen will be both challenged and supported; trafficking and localization of cell surface MMPs and a potential MMP inhibitor, RECK, will be discussed as a highly selective and cell controllable route to specificity and regulation of focal proteolysis. With many aspects of the structural biology of MMPs now well established, it is time to turn to innovative methods of studying and resolving the dynamic nature of MMPs in catalysis and in vivo by new imaging techniques. Embracement of proteomics by the protease field has, in general, been slow due to significant technical challenges. Hence, establishing the roles of MMPs in physiological processes by system-wide level investigations remains in its infancy, but will be a topic of discussion. It is hoped that these discussions and presentations will further nucleate the field to research the roles of metalloproteinases and their impact on the substrate degradome in physiological processes at a system-wide level as an essential prerequisite to understanding their role in pathology.