Matrix Biology Research Articles

Introduction

These are the proceedings of an international meeting on “Structural Aspects of the Intercellular Matrices of Plants and Animals”, June 23–26, 2008 in St. Tropez, France. The meeting was sponsored by the Matrix Biology Institute (Edgewater, New Jersey, USA) and Phillips Hydrocolloids Research Ltd, London, UK, and organized by Janet Denlinger and Glyn Phillips (co-editors of this Special Issue), with Endre A. Balazs at Villas Nifnaha and Hylan, Parc de la Moutte, St. Tropez, France.

Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with mortality in haemodialysis patients

Vascular calcification and accelerated atherosclerosis are major causes of death in haemodialysis (HD) patients. Matrix metalloproteinases (MMPs) are a family of enzymes, involved in the biology of extracellular matrix and in atherogenesis. MMP1 and MMP3 contribute to the enlargement and instability of atherosclerotic plaque, respectively. The common polymorphisms on MMP1 (2G/2G) and MMP3 (6A/6A) gene promoters have been related to increased coronary artery calcification and to carotid artery stenosis. The aim of this study was to evaluate the association of MMP1 and MMP3 polymorphisms with end-stage renal failure (ESRD) and all-cause mortality risk in HD. Ninety-nine HD patients, followed-up for 36 months, and 133 matched controls were genotyped for the two polymorphisms. HD patients' characteristics were age 64 +/- 13 years, males 64%, diabetic 24%, hypertensive 62%, smokers 38%, dyslipidaemic 28%, all undergoing standard HD thrice weekly. ESRD was strongly associated with the combination of 2G/2G and 6A/6A homozygosity: OR 2.57 (0.95-7.4), P = 0.037, but not with isolated 2G/2G and 6A/6A homozygosity (P = 0.09 and P = 0.11, respectively). Isolated 2G/2G was associated with all-cause mortality risk independently from age, gender, diabetes, hypertension, smoking, dyslipidaemia, C-reactive protein, albumin, dialysis vintage and history of cardio-vascular disease: HR 2.96 (1.29-6.80), P = 0.01. A trend for the association of mortality and isolated 6A/6A homozygosity was also observed: HR 3.01 (0.88-10.26), P = 0.078. Combination of 2G/2G and 6A/6A homozygosity significantly increased the mortality risk in the same Cox regression model: HR 4.69 (1.72-12.81), P = 0.003. In this study, we demonstrated for the first time that MMP-1 and MMP-3 gene polymorphisms are negative prognostic risk factors for all-cause mortality in HD patients, independently from traditional risk factors. These data may have important implications for better understanding the pathogenesis of the increased mortality in HD patients.

Evolving Concepts of Cardiac Valve Dynamics

Considerable progress has been made in recent years toward elucidating a conceptual framework that integrates the dynamic functional structure, mechanical properties, and pathobiological behavior of the cardiac valves. This communication reviews the evolving paradigm of a continuum of heart valve structure, function, and pathobiology and explores its implications. Specifically, we discuss (1) the interactions of valve biology and biomechanics (eg, correlations of function with structure at the cell, tissue, and organ levels and mechanical considerations, development, endothelial cell and interstitial cell biology, extracellular matrix biology, homeostasis, and adaptation to environmental change); (2) mechanisms of disease (eg, valve cell and matrix pathobiology in congenital anomalies, aortic valve calcification, and mitral valve prolapse); (3) considerations in replacement and repair (eg, cell/matrix biology of tissue valve substitutes and their degeneration and durability of repairs); and (4) the potential for tissue engineering approaches to therapeutic regeneration of the cardiac valves. Opportunities for research and clinical translation are highlighted.

Healing beauty? More biotechnology cosmetic products that claim drug-like properties reach the market.

Beauty—as the saying goes—is in the eye of the beholder, though this relativistic insight has not stopped humans from spending more than 6,000 years striving to artificially enhance their looks. From Ancient Egypt and Sumer until today, the quest for beauty is recorded in our literature, music and art. Even today, many women and men devote considerable amounts of time and money to selecting and applying the right combination of cosmetic products, and thus drive a huge—and still growing—cosmetics industry. In turn, cosmetics companies, in bids to outdo their competitors, are increasingly using the results of basic research in the biological and chemical sciences to create more sophisticated products that promise little less than everlasting beauty. The latest wave of cosmetics are based on advanced research that includes the use of biotechnology‐derived ingredients, genetic profiling for individual skin‐care or nutritional regimes, stem‐cell‐based products and therapies to regenerate ageing tissues, or cell and tissue engineering for cosmetic purposes. “Cosmetics will take advantage from those technologies that will allow one to achieve observable results upon topical application,” commented Paolo Giacomoni, the head of research at a large cosmetics company. “Stabilized enzymes used in topical applications will help to repair [damage] after exposure to solar radiation, or to digest pigments in age spots. Appropriate polymers will tighten the skin and reduce the appearance of lines and wrinkles, or prolong moisturization.” As a consequence of this increasing application of science to beauty, the line between cosmetic and medical research is becoming blurred; the laboratories of major cosmetic companies perform cutting‐edge research in areas such as matrix biology, antioxidants and ageing processes. In addition to the goal of making women and men look younger, this research also benefits the development of therapies against a range of serious disorders. Vice versa, various biotechnology companies—such as those …

Fibrosis, chronic inflammation and new pathways for drug discovery

Recent studies have challenged the conventional hypothesis that inflammation is the major player in the fibrosis cascade. Emerging evidence points to a critical role for interactions between tissue-resident and infiltrating, non-resident cells, in mediating fibrotic responses. Improved understanding of the biology of extracellular matrix (ECM) remodeling and the pathways that regulate assembly of the ECM and its interactions with growth factors/cytokines have led to the identification of new and attractive therapeutic targets. These include molecules that regulate fibrocytic cell infiltration, epithelial and myofibroblast differentiation, ECM synthesis and degradation. However, it is imperative that these new therapies be timed and compartmentalized to target the tissue of interest, as the dynamics of cellular differentiation and ECM remodeling may be different between organ systems. This review will summarize the current understanding of the mechanisms involved in the development of fibrosis, based on recent in vitro and in vivo studies, and comment on novel molecular pathways for drug discovery.

A tribute to Elizabeth D. Hay, 1927–2007

A tribute to Elizabeth D. Hay, 1927–2007

Collagen-related gene and protein expression changes in the lung in response to chronic hypoxia

Collagen accumulation likely contributes to increased vascular and airway impedance in hypoxia-induced pulmonary hypertension (HPH). Collagen exists in multiple subtypes and can accumulate via increased synthesis or decreased degradation. To better understand the individual contributions of fibrillar (FB) and basement membrane (BM) collagen, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) to pulmonary vascular and airway remodeling in HPH, we investigated the temporal changes in gene and protein expression in the lungs of mice exposed to hypoxia for 0, 3, 6, 10 and 15 days. The earliest and largest change in gene expression was of type I FB collagen, which was significantly increased over control levels at 6, 10 and 15 days of hypoxia (p < 0.05). Type III FB and type IV BM collagen were increased at 10 and 15 days of hypoxia (p < 0.05); MMP and TIMP gene expression levels were typically higher but sometimes lower than control levels at various time points. Collagen protein content was increased in whole lungs as early as 6 days of hypoxia and increased monotonically with longer exposures. However, neither qualitative nor semi-quantitative analysis of immunohistochemistry demonstrated accumulation of type I FB collagen in compartments of the lung other than large airways, suggesting that other collagen subtypes may be important contributors to collagen protein accumulation. These results provide insight into the patterns of gene and protein expression relevant to collagen accumulation in the lung in response to chronic hypoxia, through which we can develop a better understanding of the time course of changes in matrix biology and biomechanics that occur in HPH.

British Society for Matrix Biology and European Tissue Society Meeting, Oxford, 31 March-2 April 1999

British Society for Matrix Biology and European Tissue Society Meeting, Oxford, 31 March-2 April 1999

Treatment of COPD: a matrix perspective.

Fundamental physical properties, such as the intrinsic recoil of the lung, are governed by the extracellular matrix. The prototypical roles of the matrix proteins, collagen and elastin, in pulmonary fibrosis and emphysema have long been recognized, and much research effort has been devoted to understanding mechanisms of extracellular matrix synthesis and turnover in the lung. Yet, despite extensive knowledge of the biochemical properties of collagen and elastin, none of the present clinical strategies for treating COPD directly target the extracellular matrix. From a matrix perspective, therapeutic interventions that limit elastic fiber destruction and/or restore function to damaged alveolar units merit particular consideration as clinical strategies for treating the emphysema component of COPD. Effective treatment of the bronchiolar component of COPD requires a better understanding of the relationship between airway fibrosis and airflow obstruction. Translating basic knowledge of extracellular matrix biology into the clinical venue will be essential in the development of new approaches to COPD treatment.

Extracellular Matrix of the Female Reproductive Tract

ture of the membranes and mechanotransduction or solid-state signaling, the role of 3-dimension culture systems in reproduction, biomechanics, ECM remodeling, and the role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function and changes in ECM in uterine fibroids were a few of the topics presented and discussed.This supplement presents some of the articles presented at the meeting that stimulated discussion. We hope that they will serve the same purpose for the readers of this publication. Finally, the ECMFRT is maturing and changing. It is time for a new conference format and a larger audience. Accordingly, the leadership of the ECMFRT will organize a new Extracellular Matrix Satellite Meeting at the Society for Gynecologic Investigation (SGI) annual meeting.Although the format of the satellite meetings is vastly different from the past meetings, the same spirit of intellectual curiosity and stimulating discussion will continue. We will gain by having more scientists, especially younger scientists, in attendance and the opportunity to expose the exciting field of ECM to the entire SGI membership. The format of 6 speakers in the satellite meetings provides for cross-talk between scientific areas because it allows for the ability of attendees at one meeting to attend presentations relevant to them at other satellite meetings.Thus, we hope that we will be able to generate even more interest in matrix biology. EDITORIAL

Transglutaminase 2 Undergoes a Large Conformational Change upon Activation

Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-Å resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.

Factors influencing the expression of dental extracellular matrix biomineralization.

The forming tooth organ provides a number of opportunities to investigate the cellular and molecular biology of cell-mediated extracellular matrix (ECM) biomineralization. Regulatory processes associated with tooth formation are being investigated by identifying when and where cell adhesion molecules (CAMs), substrate adhesion molecules (SAMs), dentine phosphoprotein and enamel gene products are expressed during sequential developmental stages. In vitro organotypic culture studies in serumless, chemically-defined medium, have shown that instructive and permissive signalling are required for both morphogenesis and cytodifferentiation. Intrinsic developmental instructions (autocrine and paracrine factors) act independently of long-range hormonal or exogenous growth factors and mediate morphogenesis from the initiation of the dental lamina to the crown stages of tooth development. This review summarizes the results of studies using experimental embryology, recombinant DNA technology and immunocytology to elucidate mechanisms responsive to instructive epithelial-mesenchymal interactions associated with ameloblast differentiation, odontoblast differentiation, and dentine and enamel ECM biomineralization.

The role of endothelial cell attachment to elastic fibre molecules in the enhancement of monolayer formation and retention, and the inhibition of smooth muscle cell recruitment

The endothelium is an essential modulator of vascular tone and thrombogenicity and a critical barrier between the vessel wall and blood components. In tissue-engineered small-diameter vascular constructs, endothelial cell detachment in flow can lead to thrombosis and graft failure. The subendothelial extracellular matrix provides stable endothelial cell anchorage through interactions with cell surface receptors, and influences the proliferation, migration, and survival of both endothelial cells and smooth muscle cells. We have tested the hypothesis that these desired physiological characteristics can be conferred by surface coatings of natural vascular matrix components, focusing on the elastic fiber molecules, fibrillin-1, fibulin-5 and tropoelastin. On fibrillin-1 or fibulin-5-coated surfaces, endothelial cells exhibited strong integrin-mediated attachment in static conditions (82% and 76% attachment, respectively) and flow conditions (67% and 78% cell retention on fibrillin-1 or fibulin-5, respectively, at 25 dynes/cm 2), confluent monolayer formation, and stable functional characteristics. Adhesion to these two molecules also strongly inhibited smooth muscle cell migration to the endothelial monolayer. In contrast, on elastin, endothelial cells attached poorly, did not spread, and had markedly impaired functional properties. Thus, fibrillin-1 and fibulin-5, but not elastin, can be exploited to enhance endothelial stability, and to inhibit SMC migration within vascular graft scaffolds. These findings have important implications for the design of vascular graft scaffolds, the clinical performance of which may be enhanced by exploiting natural cell–matrix biology to regulate cell attachment and function.

British Society for Matrix Biology Meeting, Autumn 2006

International Journal of Experimental PathologyVolume 88, Issue 4 p. A46-A74 British Society for Matrix Biology Meeting, Autumn 2006 First published: 10 August 2007 https://doi.org/10.1111/j.1365-2613.2007.00525.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume88, Issue4August 2007Pages A46-A74 RelatedInformation

From collagen chemistry towards cell therapy - a personal journey.

The Fell-Muir Award requires the recipient to deliver a lecture and a review manuscript which provides a personal overview of significant scientific developments in the field of matrix biology over the period of the recipient's career. In this context, this review considers the collagen family of structural proteins and the advances in biochemical, molecular biological and genetic techniques which led to the elucidation of the structure, synthesis and function of this important group of extracellular matrix constituents. Particular attention is focussed on early research on the identification and assembly of the soluble precursors of collagen types I and II, and the identification of the precursor of basement membrane collagen type IV. In subsequent studies investigating the maintenance of the chick chondrocyte phenotype in culture, the influence of the extracellular milieu was found to influence markedly both cell morphology and collagen gene expression. These studies led to the discovery of collagen type X whose expression is restricted to hypertrophic chondrocytes at sites of endochondral ossification. Such research provided a prelude to investigations of mammalian endochondral ossification which is known to be aberrant in a variety of human chondrodysplasias and is reactivated in bone fracture repair and in osteoarthritis. The cloning of bovine and then human collagen type X genes facilitated studies in relevant human diseases and contributed to the discovery of mutations in the COL10A1 gene in families with metaphyseal chondrodysplasia type Schmid. Clustering of mutations in the C-terminal domain of the type X collagen molecule has now been widely documented and investigations of the pathogenic mechanisms in animal models are beginning to suggest the prospect of novel treatment strategies.

Symposium: Tendon and ligament remodelling and regeneration

Symposium: Tendon and ligament remodelling and regeneration

Factors controlling matrix turnover in health and disease

The impact of changes in matrix turnover on disease processes is gradually becoming more widely understood and appreciated. Similarly, the importance of interactions between the cellular and acellular components of any given tissue is finally being realized. An unhealthy cell does not make a healthy matrix; likewise an unhealthy matrix often leads to the demise of the cells within it, or at the very least to major changes in cell phenotype. We can therefore no longer investigate these two components in isolation, because the matrix so often contributes to cellular signalling pathways, and these in turn can lead to changes in matrix turnover. This is a long way from the traditional view of the role of the extracellular matrix, or 'ground substance', in filling the spaces between the cells and providing physical support for them. Just over 100 delegates assembled at Sheffield Hallam University for the Joint BSMB (British Society for Matrix Biology)/Biochemical Society Focused Meeting on Matrix Turnover: Mechanisms and Common Denominators on 2-3 April 2007. The stated aim of the meeting was to aid and encourage interactions between scientists working in various areas of matrix biology, and to this end there were sessions on intervertebral disc, turnover in the CNS (central nervous system), fibroses and tumour-stroma interactions, as well as a session covering general topics. The involvement of both the BSMB and Biochemical Society membership increased the potential for interactions between scientists and hopefully increased the value of the meeting for all the delegates. This issue of Biochemical Society Transactions contains papers written by those who gave oral presentations at the meeting. I think it is fair to conclude from their talks and the papers presented here that the 'common denominators' involved in matrix turnover include cytokine and growth factor signalling pathways that control the rates of matrix synthesis and breakdown, and which, in many disease processes, lead to an uncoupling of synthesis and breakdown and thereby the loss of homoeostasis. Evidently, the make-up of the matrix surrounding cells profoundly affects cell phenotype and behaviour through various signalling pathways. Numerous environmental stimuli may trigger these events, and a host of genes are undoubtedly involved in generating predisposing genotypes. Such factors appear to be common to many diseases involving matrix turnover.

Designed triple-helical peptides as tools for collagen biochemistry and matrix engineering

Collagens, characterized by a unique triple-helical structure, are the predominant component of extracellular matrices (ECMs) existing in all multicellular animals. Collagens not only maintain structural integrity of tissues and organs, but also regulate a number of biological events, including cell attachment, migration and differentiation, tissue regeneration and animal development. The specific functions of collagens are generally triggered by specific interactions of collagen-binding molecules (membrane receptors, soluble factors and other ECM components) with certain structures displayed on the collagen triple helices. Thus, synthetic triple-helical peptides that mimic the structure of native collagens have been used to investigate the individual collagen-protein interactions, as well as collagen structure and stability. The first part of this article illustrates the design of various collagen-mimetic peptides and their recent applications in matrix biology. Collagen is also acknowledged as one of the most promising biomaterials in regenerative medicine and tissue engineering. However, the use of animal-derived collagens in human could put the recipients at risks of pathogen transmission or allergic reactions. Hence, the production of safe artificial collagen surrogates is currently of considerable interest. The latter part of this article reviews recent attempts to develop artificial collagens as novel biomaterials.

The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells

AbstractThe molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell– and follicular dendritic cell–related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (TFH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published TFH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several TFH genes was validated by immunohistochemistry in AITLs. A few cases with molecular TFH-like features were identified among CD30− PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30− PTCLs-u may derive from or be related to AITL.

British Society for Matrix Biology Spring 2006 and Abstracts, Queens College, Cambridge

British Society for Matrix Biology Spring 2006 and Abstracts, Queens College, Cambridge