ÔØ ÅÒÙ×Ö ÔØ Metalloproteinases: A parade of functions in matrix biology and an outlook for the future Suneel S. Apte, William C. Parks PII: S0945-053X(15)00088-8 DOI: doi: 10.1016/j.matbio.2015.04.005 Reference: MATBIO 1165 To appear in: Matrix Biology Received date: 16 April 2015 Accepted date: 17 April 2015 Please cite this article as: Apte, Suneel S., Parks, William C., Metalloproteinases: A parade of functions in matrix biology and an outlook for the future, Matrix Biology (2015), doi: 10.1016/j.matbio.2015.04.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Metalloproteinases: a parade of functions in matrix biology and an outlook for the future Suneel S. Apte1* and William C. Parks2* 1Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA, and 2Cedars-Sinai Medical Center, Los Angeles, CA USA *Correspondences to: Suneel S. Apte, MBBS, D.Phil Department of Biomedical Engineering (ND20), Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Phone: 216 445 3278 Fax: 1 216 444 9198 Email: [email protected] William C. Parks, PhD Cedars-Sinai Medical ACCEPTEDCenter MANUSCRIPT 8700 Beverly Blvd., A9403 Los Angeles, CA 90048 USA Phone: 424-315-4307 Fax: 310-967-8370 Email: [email protected] ACCEPTED MANUSCRIPT Abstract: This issue of Matrix Biology is devoted to exploring how metalloproteinases – here inclusive of related families of extracellular proteinases – act on extracellular matrix (ECM) proteins to influence an astonishing diversity of biological systems and diseases. Since their discovery in the 1960’s, matrix metalloproteinases (MMPs) have oft and widely been considered as the principal mediators of ECM destruction. However, as becomes clear from several articles in this issue, MMPs affect processes that both promote and limit ECM assembly, structure, and quantity. Furthermore, it has become increasingly apparent that ECM proteolysis is neither the exclusive function of MMPs nor their only sphere of influence. Thus, other enzymes may be important participants in ECM proteolysis, and indeed they are. The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 repeat) proteinases, BMP/tolloid proteases, and meprins have all emerged as major mechanisms of ECM proteolysis. An aggregate view of proteolysis as an exquisitely specific and crucial post-translational modification of secreted proteins emerges from these reviews. The cumulative evidence strongly suggests that although some MMPs can and do cleave ECM components, notably fibrillar collagens, the majority of these proteinases are not key physiological participants in morphogenesis nor in control of matrix metabolism in homeostasis or disease. In contrast, deficiency of ADAMTS proteases leads to a remarkableACCEPTED array of morphogenetic MANUSCRIPT defects and connective tissue disorders consistent with a specialized role in turnover of the embryonic provisional ECM and in ECM assembly. Astacin-related proteases emerge into crucial positions in ECM assembly and turnover, although they also have numerous roles related to morphogen and growth factor regulation. To further turn the traditional view on its head, it is clear that many MMPs are key participants in many, diverse immune and inflammation processes rather than ECM proteolysis. The overlap in the activities within and between these families leads to the view that ECM proteolysis, which is indispensable for life, was over-engineered to an ACCEPTED MANUSCRIPT extraordinary extent during vertebrate evolution. That these proteinases, which likely evolved within networks regulating morphogenesis, immunity and regeneration, also participate in diseases is a side effect of human longevity. Attempts to inhibit metalloproteinases in human diseases thus require continuing appraisal of their biological roles and cautious evaluation of potential new therapeutic opportunities. Key Words: metalloproteinase, extracellular matrix, ADAMTS, merpin ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT In this Special Issue of Matrix Biology, thirty minireviews present some of the diversity of metalloproteinase functions in the context of ECM. Although this issue could not be all-inclusive, it attempts to balance physiological and disease roles and basic and translational research and features a geographic diversity of authors. This Issue represents an astonishing range of research interests. In this prefatory article, we attempt to provide an overview of the relevant historical, fundamental, and translational setting for the Issue and seek to predict where the field may be headed in the future. 1. The metalloproteinases presented in this special issue. In this issue, the articles focus on three subfamilies of metalloproteinases with demonstrated functions in ECM metabolism: the matrix metalloproteinases (MMPs, matrixins), ADAMTS proteinases, and astacins (BMP/tolloid proteases and meprins in mammals) [1]. These groups comprise numerous endopeptidases that each contain an active site Zn2+ ion (hence the prefix “metallo”) and are among nearly 200 Zn-dependent metalloproteinases found in mammals [2]. They all belong to the metzincin clan, which is characterized by a 3-histidine (His) zinc- binding catalytic motif (His-Glu-Xaa-Xaa-His + His) and a conserved methionine (Met) following the active site [3]. A glutamate (Glu) residue within the catalytic motif activates a zinc-bound H2O molecule providing the nucleophile that cleaves peptide bonds. The metzincins are eitherACCEPTED secreted or membrane MANUSCRIPT-associated (i.e., transmembrane or membrane linked via glycolipid anchors) and are synthesized as pre-pro-polypeptides. Generally speaking, although there are a few exceptions in the ADAMTS family, the propeptides inhibit proteolytic activity and must be removed from the zymogen to elicit proteolytic activity, a process termed activation [4]. Many metalloproteinase zymogens – including all ADAMTSs and about a third of the MMPs – contain a furin-recognition sequence between the pro- and catalytic domains and are activated intracellularly before secretion or at the cell surface. Although these metalloproteinases share a similar catalytic domain topology, ACCEPTED MANUSCRIPT the domains immediately downstream differ radically among the metzincin families. These structural distinctions are the defining features of the respective families [1]. Because the focus of this Issue is ECM proteolysis, we have excluded the ADAM proteinases (a disintegrin-like and metalloproteinase), which have emerged as the major force in protein ectodomain shedding from the cell surface, thereby controlling a wide range of cell signaling processes [5-7]. That said, ADAM proteinases can still interface with ECM metabolism, albeit via indirect mechanisms, such as by shedding the ectodomain of ECM receptors or influencing signaling pathways upstream of ECM homeostasis [8, 9]. Most articles in this issue focus on matrix metalloproteinases (MMPs), reflecting both their historic and current high profile in laboratory investigations. The issue features reviews on the roles for specific MMPs in acting on ECM components to control processes in stem cell biology [10, 11], muscle biology [12], central nervous system homeostasis and disease [13, 14], angiogenesis (cite: MATBIO-D-14-00118), tissue repair in skin [15] and liver [16], inflammation [17], vascular disease [18], destructive lung disease [19], and cancer [11, 20]. As stated, MMPs can affect these and other processes by proteolysis of non-ECM proteins, and discussion of these other functions and mechanisms can be found elsewhere [21-24]. Reviews by Itoh [25] and Gaffney et al. [26] reflect the considerable emphasis given to membrane-type (MT)ACCEPTED MMPs by investigators MANUSCRIPT in the MMP field. The article by Wells et al. [17] discusses the emerging role for byproducts of ECM proteolysis by MMPs – matrikines – which is also a function for several ADAMTS proteases [9]. The other MMP articles focus on a range of topics related to proteinase activity, specificity, and regulation. The importance of defining MMP-substrate interactions and inhibitory strategies is reflected in the articles by Steve van Doren [27] and Gregg Fields [28]. Key to understanding MMP function – indeed, to understanding the function of any proteinase - is identification and validation of its physiologic substrate (s), and Schlage and ACCEPTED MANUSCRIPT auf dem Keller [29] illustrate how proteomics provides a powerful, unbiased approach toward this goal. Furthermore, two articles discuss how MMPs are regulated by TIMPs [30] and by other cellular mechanisms [31]. 2. The lexicon of proteolysis. Before we continue with our overview of this Issue, we wish to discuss the commonly used terms applied to the activity of proteinases and how their meaning implies distinct biologic functions. Proteolysis is a widely used mechanisms for post-translational modification of proteins. Three words are often loosely used when discussing ECM proteolysis: turnover, remodeling, and degradation. Although each term intends to define a process that is, in