In 2010, I had the honor to serve as Guest Editor for a Special Issue of BBA-Molecular and Cell Research on Matrix Metalloproteinases (MMPs). The issue focused on the recent advances in the field of MMPs and has been among the most read issue of the BBA-MCR series. This achievement is due, without a doubt, to the merits of the scientists who contributed to the issue and who provided an insightful and provocative overview of the field. They deserve all the credit for the previous success! But it goes without saying that the fields of MMPs, specifically, and proteolysis, in general, remain research areas of broad interest because of their importance in multiple physiological and pathological processes. The involvement of MMPs in regulation of fundamental biological events is undeniable and new evidence continues to further support this assertion. Today, the MMP field is thriving with new findings, which have challenged our views on how and where these enzymes work in various biological processes and how we can target them when deregulated in disease conditions. These advances have been promoted in part by the technological advancements of the last decade in “omics” approaches, gene targeting, protein chemistry, inhibitor design, mouse models, and many others, which have left a strong and positive imprint on the MMP field, resulting in a wealth of new information. Thus, seven years later from the first MMP issue of the BBA-MCR series, the time is right to put together a new issue that brings the latest discoveries in the MMP arena to the scientific community by leading MMP experts.
The MMPs are a defined family of zinc-dependent endopeptidases, which belong to the larger metzincin superfamily of metalloproteinases. MMPs were originally identified as matrix cleaving proteases because their main substrates included components of the extracellular matrix (ECM), such as collagens. The role of MMPs as collagenolytic proteases remains one of their most critical physiological functions. By promoting the turnover of collagens, MMPs exert a direct control on the integrity of the collagenous matrix and thus they indirectly influence a myriad of cellular processes that are dictated by the biophysical properties of collagen. Considering the complex supramolecular organization of collagen molecules, the ability of MMPs to recognize and cleave collagens at specific peptide bonds is a good example of how a set of proteases evolved to manifest a highly specialized function that is unique for this enzyme family. However, the properties and features that define a true collagenase have been the subject of some debate, which have generated confusion in the field. In this series, a review from Amar et al. provides a detailed description of the enzymatic properties that define collagenolytic activity and the ability of members of the MMP family that are capable of accomplishing collagen hydrolysis. The review also summarizes current knowledge on the role of collagen catabolism in physiological and pathological conditions. Although collagenolysis remains a key function of the members of the MMP family, previous and new research has revealed that MMPs are versatile proteases, displaying enzymatic activity against a broad-spectrum of substrates, including cytoplasmic and nuclear proteins. Thus, it is clear today that the range of MMP action goes beyond the extracellular space and the cell surface. These observations have expanded the roles of MMPs in biological functions but also provided new insights into the cellular and structural mechanisms that guide MMPs to various subcellular and extracellular compartments. New areas of research focus on unveiling the trafficking, compartmentalization, and function of MMPs within and outside cells. In this issue, several reviews describe the new developments in MMP subcellular associations from the nucleus to membranes to exosomes, and how these locales impose new and unexpected targets for MMP activity and function (reviewed by Jobin et al., and by Shimoda and Khokha). These reviews summarize new information on MMP localization that has significantly changed our views on protease function. In the same vein, a review by Van Doren et al. discusses new evidence that show the ability of soluble MMPs to associate with membrane lipids through specific interactions with the catalytic domain. The new findings outlined in this review suggest that soluble MMPs may also be suited for proteolysis in lipid-rich environments. If so, this possibility may likely expand the substrate profile of the soluble MMPs, and consequently their biological functions. The omics revolution made a significant impact in identifying new substrates of MMPs by means of mass spectrometry approaches. However, new in silico tools have been developed to predict with great confidence the cleavage preferences of MMPs within the proteome. A review by Cieplak and Strongin describes the development of a new freely available software for predicting MMP cleavage, which has the potential to contribute to the identification of novel targets of MMP activity in biological processes.
Almost three decades ago, the data implicating MMPs in various pathological conditions, particularly in cancer and arthritis, promoted a major effort in the development of specific inhibitors of enzymatic activity, as potential therapeutic agents. However, clinical trials with the first generation of MMP inhibitors produced disappointing results. Subsequent research revealed the complexity of MMP action in tissues and also some of the structural constrains that impeded inhibitor selectivity. At the same time, more evidence demonstrated the importance of some MMPs as therapeutic targets, which further invigorated the search for better inhibitors. In spite of their well-established importance in many pathological conditions, it has been a challenging endeavor to develop highly specific MMP inhibitors. In this series, two reviews by Levin et al. and by Meisel and Chang provide an updated summary of the recent advancement in the field of MMP inhibitors, and importantly the recent successes in inhibitor design that have led to the discovery of highly specific compounds to target MM activity in various disease conditions.
This series bring a new update on the biological roles of MMPs, an evolving field of research that continues to produce new information and reveal the versatility and importance of MMPs in various conditions. Accumulating evidence show that MMPs through their ability to modify the ECM can impact cell senescence. This process has fundamental implications for tissue homeostasis and renewal. A review from Rodriguez et al. discusses the current knowledge on the involvement of MMPs in the process of aging, an area of research that is uncovering a direct relationship between MMPs, aging, stem cells, and neurodegenerative diseases. The role of MMPs in these processes appears to be related their ability to change the biophysical properties of the ECM and thus altering signaling pathways that are responsive to mechanosensing. How MMPs affect this fundamental process of cell physiology is a relatively new area of research that may provide new insights into MMP action. Two reviews of the series provide an update on the roles of MMPs in inflammation and cancer, two conditions that involve intense remodeling of ECM. Barbara Fingleton writes about the pro- and anti-inflammatory actions of MMPs, which have been uncovered through the identification of new MMP substrates and animal models of inflammation. The emerging picture highlights the complexity of MMP action in inflammatory processes that is context-dependent and thus cannot be generalized. A review by Turunen et al. focuses on the expression and roles of membrane-anchored MMPs, the MT-MMPs, in cancer progression. Because of their unique structure and membrane localization, the MT-MMPs are uniquely positioned to alter substrates at the cell-matrix interface, and thus contribute to multiple processes during cancer progression. This review provides an updated overview on the current state of knowledge on the expression of each member of the MT-MMP sub-family in various cancer types and the roles they play during cancer progression. As described in the review, the MT-MMPs are multifaceted proteases that influence multiple aspect of the malignant process and thus they constitute promising targets for anti-cancer therapy.
Finally, this series includes an interesting review focused on summarizing the current knowledge on the expression and structure of MMP-related proteases outside of vertebrates. Marino-Puertas et al. conducted a comprehensive survey of the literature focusing on MMPs in invertebrates, plants, fungi, viruses, protists, archaea and bacteria. They also conducted a bioinformatics search, which resulted in the identification of potential MMP-like sequences in several life forms. This review sheds light on the complex evolutionary origin of MMPs and how these unique proteases evolved to become the precise proteolytic tools that constitute major modifiers of the proteome throughout the animal kingdom.
I sincerely hope that this updated issue of the BBA-MCR series focusing on MMPs will continue the success of its predecessor published 7 years ago and again inform the scientific community of the recent advances in MMP research. Most important, I hope that the reviews, written by top leaders in the field, will raise the interest of the new generation of scientists to continue the research efforts to decipher the inner workings of these key proteases in the fundamental aspects of life.
Biography
Dr. Rafael Fridman is a Professor of Pathology and Oncology at Wayne State University who has been working in the field of Matrix Metalloproteases (MMPs) for the las 25 years. His research has focused on understanding how MMPs contribute to cancer development through their ability to regulate tumor cell-collagen interactions. In recent years, he has been investigating the cross-talk between proteolysis and collagen-initiated signaling mediated by kinase receptors.