Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Extracellular Matrix Degradation and Remodeling in Development and Disease Pengfei Lu1,2, Ken Takai2, Valerie M. Weaver3, and Zena Werb2 1Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research and Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M20 4BX, United Kingdom 2Department of Anatomy and Program in Developmental Biology, University of California, San Francisco, California 94143-0452 3Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143 Correspondence: [email protected] The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branch- ing morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnor- mal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic inter- ventions for diseases and novel strategies for tissue engineering and regenerative medicine. he extracellular matrix (ECM) forms a milieu versatile and performs many functions in addi- Tsurrounding cells that reciprocally influ- tion to its structural role. As a major component ences cellular function to modulate diverse fun- of the microenvironment of a cell, the ECM damental aspects of cell biology (Hynes 2009). takes part in most basic cell behaviors, from The diversity and sophistication of ECM cell proliferation, adhesion and migration, to components and their respective cell surface cell differentiation and cell death (Hynes receptors are among the most salient features 2009). This pleiotropic aspect of ECM function during metazoan evolution (Har-el and Tanzer depends on the highly dynamic structure of 1993; Hutter et al. 2000; Whittaker et al. 2006; ECM and its remodeling as an effective me- Engler et al. 2009; Huxley-Jones et al. 2009; chanism whereby diverse cellular behaviors Ozbek et al. 2010). The ECM is extremely can be regulated. This concept is particularly Editors: Richard O. Hynes and Kenneth M. Yamada Additional Perspectives on Extracellular Matrix Biology available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005058 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005058 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press P. Lu et al. important when considering processes and cell of cell behaviors can be deployed by exploiting behaviors that need to be deployed promptly the important roles of ECM dynamics to build and transiently and wherein cell–cell and vertebrate organs and maintain their func- cell–matrix interactions are constantly chang- tions, and how deregulation of ECM dynamics ing (Daley et al. 2008). contributes to the initiation and progression ECM dynamics are a feature of tissues of human cancer. wherein radical remodeling occurs, such as dur- ing metamorphosis of insects and amphibians PLAYERS IN ECM DEGRADATION AND or remodeling of the adult bone and mammary REMODELING gland, and in developmental processes, includ- ing neural crest migration, angiogenesis, tooth The ECM is composed of a large collection of and skeletal development, branching morpho- biochemically and structurally diverse com- genesis, maturation of synapses, and the nerv- ponents. Biochemically, these components can ous system (Berardi et al. 2004; Fukumoto and be divided into proteins, proteoglycans, and Yamada 2005; Page-McCaw et al. 2007; Zim- glycoproteins, each of which has diverse sub- mermann and Dours-Zimmermann 2008). categories of components and varying physical ECM dynamics can result from changes and biochemical properties. Some of the ECM of ECM composition, for example, because proteins, including fibrillar collagens and of altered synthesis or degradation of one or elastin, form fibrils from protein monomers more ECM components, or in architecture and contribute the major tensile strength and because of altered organization. Mounting viscoelasticity of the tissue. Other proteins, evidence has shown how individual ECM such as fibronectin, laminin, and nidogen, components are laid down, cross-linked, and also participate in building the matrix network organized together via covalent and noncova- as connectors or linking proteins (Vakonakis lent modifications and how they can greatly and Campbell 2007; Daley et al. 2008). influence the fundamental aspects of cell behav- ior (Lopez et al. 2008; Engler et al. 2009; Egeblad Protein Components of the ECM Are et al. 2010b). This higher level of ECM organi- Degraded by Proteinases zation is also dynamic and subject to sustained remodeling as mediated by reciprocal interac- An effective strategy to remodel the ECM is by tions between the ECM and its resident cellular removal of one or more of its components. components (Daley et al. 2008). Understand- This is necessary during profound tissue ably, ECM dynamics are tightly regulated to remodeling processes such as insect and am- ensure normal development, physiology, and phibian metamorphosis or mammary gland robustness of organ systems. This is achieved involution (Sternlicht and Werb 2001). In these by redundant mechanisms to modulate the cases, massive tissues are replaced by new ones. expression and function of ECM modifying In most other cases, however, tissue remodeling enzymes at multiple levels. When such control is much less discernible with spatially restricted mechanisms are corrupted, ECM dynamics cleavage, deposition, or rearrangement of its become deregulated, leading to various human components (Egeblad and Werb 2002). congenital defects and diseases, including All the protein components outside or cancer. inside a cell are subject to degradation and Here, we examine the players involved in modification. The most significant enzymes ECM remodeling and how they are tightly regu- in ECM remodeling are metalloproteinases lated to achieve a delicate balance between (Cawston and Young 2010). Two main fam- stability and remodeling of the ECM. We focus ilies of metalloproteinases, including matrix on the cellular and molecular mechanisms metalloproteinase (MMP) and a disintegrin through which ECM dynamics influence cellu- and metalloproteinase with thrombospondin lar behaviors. We illustrate how a wide variety motifs (ADAMTS) families, are specialized in 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005058 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press ECM Degradation and Remodeling degrading the ECM. Serine proteinases, which closely related metalloproteinases (Table 1). As include plasmin and cathepsin G, are active at their names indicate, ADAMs and ADAMTSs neutral pH and also degrade ECM protein share several structural domains, including the components extracellularly. In contrast, cys- prodomain, disintegrin domain, which binds teine, aspartate, and threonine proteinases are to integrins and prevents cell–cell interac- predominantly active at acidic pH and mainly tions, and the metalloproteinase domain. Unlike digest intracellular proteins (Cawston and ADAMs, however, ADAMTSs do not have a Young 2010). However, the cysteine proteases cysteine-rich domain, an epidermal growth- cathepsins B and L can be secreted outside the factor-like domain, or a cytoplasmic tail. Instead, cell and digest the ECM as well (Green and ADAMTSs have a thrombospondin type-1 Lund 2005). (TSP-1) repeat, a Cys domain, and one or There are about 23 members in the MMP more additional TSP-1 repeats (Apte 2009). As family in vertebrates, all sharing a self-inhibi- membrane proteins expressed at the cell surface, tory prodomain at the amino terminus, a ADAMs are often involved with cytokine proc- catalytic domain, a flexible hinge motif, and a essing and growth factor receptor shedding hemopexin domain at the carboxyl terminus (Murphy 2008). ADAM-17, for example, can (Page-McCaw et al. 2007). Most of the MMPs release TNF-a from the cell surface. In contrast, have the basic three-domain structures, whereas ADAMTSs are mainly responsible for degrada- others have certain variations: MMP-2 and tion of ECM components, particularly proteo- MMP-9, for instance, have fibronectin type II glycans. Indeed, ADAMTS-1, -4, -5, -8, -9, repeats inserted in the catalytic domain to -15, -16, and -18 are regarded as proteoglyca- mediate collagen binding (Table 1). Although nases because they can degrade aggrecan, ver- most MMPs are secreted molecules, the sican, brevican, and other proteoglycans. In membrane-type MMPs (MT-MMPs; MMP- contrast, ADAMTS-2 participates in the re- 14, -15, -23, and -24) have