The extracellular matrix in multiple sclerosis pathology

The extracellular matrix (ECM) is a substrate upon which cells migrate, proliferate and differentiate. It is involved in the maintenance of cytoarchitecture, regulation of homeostasis, and it influences interactions between cells and molecules via specific receptors. Although a substantial body of knowledge has accumulated concerning the role of the ECM in peripheral tissues, little is known of the structure and function of the ECM in the CNS. However, marked changes in the expression of ECM constituents have been documented in various neurological disorders, including multiple sclerosis. This review focuses on the structure and function of the ECM in the CNS and in particular on the occurrence and involvement of ECM changes in the pathology of multiple sclerosis. Increased knowledge of the expression and functional role of ECM proteins in the CNS can lead to a better understanding of complex neurobiological processes both under normal as well as pathological conditions.     

Bacterial adhesion to animal tissues: protein determinants for recognition of extracellular matrix components

The extracellular matrix (ECM) is present within all animal tissues and organs. Actually, it surrounds the eukaryotic cells composing the four basic tissue types, i.e. epithelial, muscle, nerve and connective. ECM does not solely refer to connective tissue but composes all tissues where its composition, structure and organization vary from one tissue to another. Constituted of the four main fibrous proteins, i.e. collagen, fibronectin, laminin and elastin, ECM components form a highly structured and functional network via specific interactions. From the basement membrane to interstitial matrix, further heterogeneity exists in the organization of the ECM in various tissues and organs also depending on their physiological state. Back to a molecular level, bacterial proteins represent the most significant part of the microbial surface components recognizing adhesive matrix molecules (MSCRAMM). These cell surface proteins are secreted and localized differently in monoderm and diderm–LPS bacteria. While one collagen‐binding domain (CBD) and different fibronectin‐binding domains (FBD1 to 8) have been registered in databases, much remains to be learned on specific binding to other ECM proteins via single or supramolecular protein structures. Besides theinteraction of bacterial proteins with individual ECM components, this review aims at stressing the importance of fully considering the ECM at supramolecular, cellular, tissue and organ levels. This conceptual view should not be overlooked to rigorously comprehend the physiology of bacterial interaction from commensal to pathogenic species.     

The extracellular matrix as a scaffold for tissue reconstruction

The extracellular matrix (ECM) consists of a complex mixture of structural and functional proteins and serves an important role in tissue and organ morphogenesis, maintenance of cell and tissue structure and function, and in the host response to injury. Xenogeneic and allogeneic ECM has been used as a bioscaffold for the reconstruction of many different tissue types in both pre-clinical and human clinical studies. Common features of ECM-associated tissue remodeling include extensive angiogenesis, recruitment of circulating progenitor cells, rapid scaffold degradation and constructive remodeling of damaged or missing tissues. The ECM-induced remodeling response is a distinctly different phenomenon from that of scar tissue formation.     

The developmental roles of the extracellular matrix: beyond structure to regulation

Cells in multicellular organisms are surrounded by a complex three-dimensional macromolecular extracellular matrix (ECM). This matrix, traditionally thought to serve a structural function providing support and strength to cells within tissues, is increasingly being recognized as having pleiotropic effects in development and growth. Elucidation of the role that the ECM plays in developmental processes has been significantly advanced by studying the phenotypic and developmental consequences of specific genetic alterations of ECM components in the mouse. These studies have revealed the enormous contribution of the ECM to the regulation of key processes in morphogenesis and organogenesis, such as cell adhesion, proliferation, specification, migration, survival, and differentiation. The ECM interacts with signaling molecules and morphogens thereby modulating their activities. This review considers these advances in our understanding of the function of ECM proteins during development, extending beyond their structural capacity, to embrace their new roles in intercellula signaling.     

Functional role of periostin in development and wound repair: implications for connective tissue disease

Integrity of the extracellular matrix (ECM) is essential for maintaining the normal structure and function of connective tissues. ECM is secreted locally by cells and organized into a complex meshwork providing physical support to cells, tissues, and organs. Initially thought to act only as a scaffold, the ECM is now known to provide a myriad of signals to cells regulating all aspects of their phenotype from morphology to differentiation. Matricellular proteins are a class of ECM related molecules defined through their ability to modulate cell-matrix interactions. Matricellular proteins are expressed at high levels during development, but typically only appear in postnatal tissue in wound repair or disease, where their levels increase substantially. Members of the CCN family, tenascin-C, osteopontin, secreted protein acidic rich in cysteine (SPARC), bone sialoprotein, thrombospondins, and galectins have all been classed as matricellular proteins. Periostin, a 90 kDa secreted homophilic cell adhesion protein, was recently added to matricellular class of proteins based on its expression pattern and function during development as well as in wound repair. Periostin is expressed in connective tissues including the periodontal ligament, tendons, skin and bone, and is also prominent in neoplastic tissues, cardiovascular disease, as well as in connective tissue wound repair. This review will focus on the functional role of periostin in tissue physiology. Fundamentally, it appears that periostin influences cell behaviour as well as collagen fibrillogenesis, and therefore exerts control over the structural and functional properties of connective tissues in both health and disease. Periostin is a novel matricellular protein with close homology to Drosophila fasciclin 1. In this review, the functional role of periostin is discussed in the context of connective tissue physiology, in development, disease, and wound repair.     

Unraveling the human bone microenvironment beyond the classical extracellular matrix proteins: a human bone protein library

A characteristic feature of bone, differentiating it from other connective tissues, is the mineralized extracellular matrix (ECM). Mineral accounts for the majority of the bone tissue volume, being the remainder organic material mostly derived from collagen. This, and the fact that only a limited number of noncollagenous ECM proteins are described, provides a limited view of the bone tissue composition and bone metabolism, the more so considering the increasing understanding of ECM significance for cellular form and function. For this reason, we set out to analyze and extensively characterize the human bone proteome using large-scale mass spectrometry-based methods. Bone samples of four individuals were analyzed identifying 3038 unique proteins. A total of 1213 of these were present in at least 3 out of 4 bone samples. For quantification purposes, we were limited to noncollagenous proteins (NCPs) and we could quantify 1051 NCPs. Most classical bone matrix proteins mentioned in literature were detected but were not among the highly abundant ones. Gene ontology analyses identified high-abundance groups of proteins with a functional link to mineralization and mineral metabolism such as transporters, pyrophosphatase activity, and Ca(2+)-dependent phospholipid binding proteins. ECM proteins were as well overrepresented together with nucleosome and antioxidant activity proteins, which have not been extensively characterized as being important for bone. In conclusion, our data clearly demonstrates that human bone tissue is a reservoir of a wide variety of proteins. In addition to the classical osteoblast-derived ECM, we have identified many proteins from different sources and of unknown function in bone. Thus, this study represents an informative library of bone proteins forming a source for novel bone formation modulators as well as biomarkers for bone diseases such as osteoporosis.     

Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance

The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-β and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury.     

Extracellular vesicles are integral and functional components of the extracellular matrix

Extracellular vesicles (EV) are small plasma membrane-derived particles released into the extracellular space by virtually all cell types. Recently, EV have received increased interest because of their capability to carry nucleic acids, proteins, lipids and signaling molecules and to transfer their cargo into the target cells. Less attention has been paid to their role in modifying the composition of the extracellular matrix (ECM), either directly or indirectly via regulating the ability of target cells to synthesize or degrade matrix molecules. Based on recent results, EV can be considered one of the structural and functional components of the ECM that participate in matrix organization, regulation of cells within it, and in determining the physical properties of soft connective tissues, bone, cartilage and dentin. This review addresses the relevance of EV as specific modulators of the ECM, such as during the assembly and disassembly of the molecular network, signaling through the ECM and formation of niches suitable for tissue regeneration, inflammation and tumor progression. Finally, we assess the potential of these aspects of EV biology to translational medicine.     

细胞外基质蛋白质预测工具研究进展

细胞外基质蛋白质在细胞的一系列生物过程中发挥着重要作用,它的异常调节会导致很多重大疾病。理论细胞外基质蛋白质参考数据是实现细胞外基质蛋白质高效鉴定的基础,研究者们已经基于机器学习的方法开发出一系列的细胞外基质蛋白质预测工具。文中首先阐述了基于机器学习模型构建细胞外基质蛋白质预测工具的基本流程,之后以工具为单位总结了已有细胞外基质蛋白质预测工具的研究成果,最后提出了细胞外基质蛋白质预测工具目前面临的问题和可能的优化方法。     

Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal

The thrombospondins are a family of secreted, oligomeric glycoproteins that interact with cell surfaces, multiple components of the extracellular matrix, growth factors and proteases. These interactions underlie complex roles in cell interactions and tissue homeostasis in animals. Thrombospondins have been grouped functionally with SPARCs, tenascins and CCN proteins as adhesion-modulating or matricellular components of the extracellular milieu. Although all these multi-domain proteins share various commonalities of domains, the grouping is not based on structural homologies. Instead, the terms emphasise the general observations that these proteins do not form large-scale ECM structures, yet act at cell surfaces and function in coordination with the structural ECM and associated extracellular proteins. The designation of adhesion-modulation thus depends on observed tissue and cell culture ECM distributions and on experimentally identified functional properties. To date, the evolutionary relationships of these proteins have not been critically compared: yet, knowledge of their evolutionary histories is clearly relevant to any consideration of functional similarities. In this article, we survey briefly the structural and functional knowledge of these protein families, consider the evolution of each family, and outline a perspective on their functional roles.     

SPARC/osteonectin in mineralized tissue

Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM40) is one of the most abundant non-collagenous protein expressed in mineralized tissues. This review will focus on elucidating functional roles of SPARC in bone formation building upon results from non-mineralized cells and tissues, the phenotype of SPARC-null bones, and recent discoveries of human diseases with either dysregulated expression of SPARC or mutations in the gene encoding SPARC that give rise to bone pathologies. The capacity of SPARC to influence pathways involved in extracellular matrix assembly such as procollagen processing and collagen fibril formation as well as the capacity to influence osteoblast differentiation and osteoclast activity will be addressed. In addition, the potential for SPARC to regulate cross-linking of extracellular matrix proteins by members of the transglutaminase family of enzymes is explored. Elucidating defined biological functions of SPARC in terms of bone formation and turnover are critical. Further insight into specific cellular mechanisms involved in the formation and homeostasis of mineralized tissues will lead to a better understanding of disease progression.     

Glycation-induced modification of tissue-specific ECM proteins: A pathophysiological mechanism in degenerative diseases

BackgroundGlycation driven generation of advanced glycation end products (AGEs) and their patho-physiological role in human degenerative diseases has remained one of the thrust areas in the mainstream of disease biology. Glycation of extracellular matrix (ECM) proteins have deleterious effect on the mechanical and functional properties of tissues. Owing to the adverse pathophysiological concerns of glycation, there is a need to decipher the underlying mechanisms.Scope of reviewAGE-modified ECM proteins affect the cell in the vicinity by altering protein structure-function, matrix-matrix or matrix-cell interaction and by activating signalling pathway through receptor for AGE. This review is intended for addressing the AGE-induced modification of tissue-specific ECM proteins and its implication in the pathogenesis of various organ-specific human ailments.Major conclusionsThe glycation affects the canonical cell behaviour due to alteration in the interaction of glycated ECM with receptors like integrins and discodin domain, and the signalling cues generated subsequently affect the downstream signalling pathways. Consequently, the variation of structural and functional properties of tissues due to matrix glycation helps in the initiation or progression of the disease condition.General significanceThis review offers comprehensive knowledge about the remodelling of glycation induced ECM and tissue-specific pathological concerns. As glycation of ECM affects the normal tissues and cell behaviour, the scientific discourse may also provide cues for developing candidate drugs that may help in attenuating the adverse effects of AGEs and perhaps open a research window of tailoring novel strategies for the management of glycation induced human degenerative diseases.     

Bone morphogenetic protein-1/Tolloid-like proteinases process dentin matrix protein-1

Bone morphogenetic protein-1 (BMP-1)/Tolloid-like metalloproteinases play key roles in formation of mammalian extracellular matrix (ECM), through the biosynthetic conversion of precursor proteins into their mature functional forms. These proteinases probably play a further role in formation of bone through activation of transforming growth factor beta-like BMPs. Dentin matrix protein-1 (DMP1), deposited into the ECM during assembly and involved in initiating mineralization of bones and teeth, is thought to undergo proteolysis in vivo to generate functional cleavage fragments found in extracts of mineralized tissues. Here, we have generated recombinant DMP1 and demonstrate that it is cleaved, to varying extents, by all four mammalian BMP-1/Tolloid-like proteinases, to generate fragments similar in size to those previously isolated from bone. Consistent with possible roles for the BMP-1/Tolloid-like proteinases in the physiological processing of DMP1, NH2-terminal sequences of products generated by BMP-1 cleavage of DMP1 match those predicted from processing at the predicted DMP1 site that shows greatest cross-species conservation of sequences. Moreover, fibroblasts derived from mouse embryos homozygous null for genes encoding three of the four mammalian BMP-1/Tolloid-like proteinases appear to be deficient in processing of DMP1. Thus, a further role for BMP-1-Tolloid-like proteinases in formation of mineralized tissues is indicated, via proteolytic processing of DMP1.     

Extracellular S100A4 as a key player in fibrotic diseases

Fibrosis is characterized by fibroblast activation, extracellular matrix (ECM) accumulation and infiltration of inflammatory cells that sometimes leads to irreversible organ dysfunction. Considerable evidence now indicates that inflammation plays a critical role in the initiation and progression of organ fibrosis. S100A4 protein, a ubiquitous member of the S100 family, has recently been discovered as a potential factor implicated in fibrotic diseases. S100A4 protein is released at inflammatory site and has a certain biological function to promote cell motility, invasion, ECM remodelling, autophagy and angiogenesis. In addition, extracellular S100A4 is also a potential causation of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions. Elevated S100A4 level in patients’ serum closely correlates with disease activity in several fibrotic diseases and serves as a useful biomarker for diagnosis and monitoring disease progression. Analyses of knockout mouse models have identified a functional role of extracellular S100A4 protein in fibrotic diseases, suggesting that suppressing its expression, release or function might be a promising therapeutic strategy. This review will focus on the role of extracellular S100A4 as a key regulator of pro-inflammatory signalling pathways and its relative biological processes involved in the pathogenesis of fibrosis.     

Extracellular matrix protein 1 interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2

Extracellular matrix protein 1 (ECM1), a widely expressed glycoprotein, has been shown to harbor mutations in lipoid proteinosis (LP), an autosomal recessive disorder characterized by profound alterations in the extracellular matrix of connective tissue. The biological function of ECM1 and its role in the pathomechanisms of LP are unknown. Fibulins comprise a family of extracellular matrix components, and the prototype of this family, fibulin-1, is expressed in various connective tissues and plays a role in developmental and pathologic processes. In this study, we demonstrate that ECM1, and specifically the second tandem repeat domain which is alternatively spliced, interacts with the C-terminal segments of fibulins 1C and 1D splice variants which differ in their C-terminal domain III. The interactions were detected by yeast two-hybrid genetic system and confirmed by co-immunoprecipitations. Kinetics of the binding between ECM1 and fibulin-1D, measured by biosensor assay, revealed a K(d) of 5.71 x 10(-8) M, indicating a strong protein-protein interaction. Since distinct splice variants of ECM1 and fibulin-1 have been shown to be co-expressed in tissues affected in LP, we propose that altered ECM1/fibulin-1 interactions may play a role in the pathogenesis of this disease as well as in a number of processes involving the extracellular matrix of connective tissues.     

Localizing matrix metalloproteinase activities in the pericellular environment

Matrix metalloproteinases (MMPs) are a group of structurally related proteolytic enzymes containing a zinc ion in the active site. They are secreted from cells or bound to the plasma membrane and hydrolyze extracellular matrix (ECM) and cell surface-bound molecules. They therefore play key roles in morphogenesis, wound healing, tissue repair and remodeling in diseases such as cancer and arthritis. Although the cell anchored membrane-type MMPs (MT-MMPs) function pericellularly, the secreted MMPs have been considered to act within the ECM, away from the cells from which they are synthesized. However, recent studies have shown that secreted MMPs bind to specific cell surface receptors, membrane-anchored proteins or cell-associated ECM molecules and function pericellularly at focussed locations. This minireview describes examples of cell surface and pericellular partners of MMPs, as well as how they alter enzyme function and cellular behaviour.     

An Introductory Review of Cell Mechanobiology

Mechanical loads induce changes in the structure, composition, and function of living tissues. Cells in tissues are responsible for these changes, which cause physiological or pathological alterations in the extracellular matrix (ECM). This article provides an introductory review of the mechanobiology of load-sensitive cells in vivo, which include fibroblasts, chondrocytes, osteoblasts, endothelial cells, and smooth muscle cells. Many studies have shown that mechanical loads affect diverse cellular functions, such as cell proliferation, ECM gene and protein expression, and the production of soluble factors. Major cellular components involved in the mechanotransduction mechanisms include the cytoskeleton, integrins, G proteins, receptor tyrosine kinases, mitogen-activated protein kinases, and stretch-activated ion channels. Future research in the area of cell mechanobiology will require novel experimental and theoretical methodologies to determine the type and magnitude of the forces experienced at the cellular and sub-cellular levels and to identify the force sensors/receptors that initiate the cascade of cellular and molecular events     

Border patrol: Insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders

The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (> 200 nm) and oldest (> 550 M years) extracellular matrix molecules. In vertebrates, perlecan's five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II–V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders.     

Approaches in extracellular matrix engineering for determination of adhesion molecule mediated single cell function

The native extracellular matrix (ECM) and the cells that comprise human tissues are together engaged in a complex relationship; cells alter the composition and structure of the ECM to regulate the material and biologic properties of the surrounding environment while the composition and structure of the ECM modulates cellular processes that maintain healthy tissue and repair diseased tissue. This reciprocal relationship occurs via cell adhesion molecules (CAMs) such as integrins, selectins, cadherins and IgSF adhesion molecules. To study these cell-ECM interactions, researchers use two-dimensional substrates or three-dimensional matrices composed of native proteins or bioactive peptide sequences to study single cell function. While two-dimensional substrates provide valuable information about cell-ECM interactions, three-dimensional matrices more closely mimic the native ECM; cells cultured in three-dimensional matrices have demonstrated greater cell movement and increased integrin expression when compared to cells cultured on two-dimensional substrates. In this article we review a number of cellular processes (adhesion, motility, phagocytosis, differentiation and survival) and examine the cell adhesion molecules and ECM proteins (or bioactive peptide sequences) that mediate cell functionality.