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Extracellular Matrices

New sub-forum for discussion on topics related to extracellular matrices and connective tissues
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Osmotic surveillance mediates fast ...


by jonmoulton
Dec 23, 2014, 17:33 PM

Biomaterials and Tissue Engineering

Biomaterials and Tissue Engineering
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ImageJ bone modelling ( Morphometri ...


by cemil92
Nov 21, 2014, 15:49 PM

3D Culture

Matrigel, soft agar, collagen, angiogenesis, migration . . .
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3D culture of colorectal cells- sug ...


by Synthecon 3D
Apr 02, 2015, 17:56 PM



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Matrix Biology
Publication date: Available online 12 April 2018
Source:Matrix Biology

Author(s): Chien-Jung Lin, Chieh-Yu Lin, Nathan O. Stitziel

Aortic aneurysms are morbid conditions that can lead to rupture or dissection and are categorized as thoracic (TAA) or abdominal aortic aneurysms (AAA) depending on their location. While AAA shares overlapping risk factors with atherosclerotic cardiovascular disease, TAA exhibits strong heritability. Human genetic studies in the past two decades have successfully identified numerous genes involved in both familial and sporadic forms of aortic aneurysm. In this review we will discuss the genetic basis of aortic aneurysm, focusing on the extracellular matrix and how insights from these studies have informed our understanding of human biology and disease pathogenesis.





Publication date: Available online 12 April 2018
Source:Matrix Biology

Author(s): Detlef Schuppan, Muhammad Ashfaq-Khan, Ai Ting Yang, Yong Ook Kim

Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and extracellular matrix (ECM)-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of noninvasive biomarkers of fibrosis, fibrogenesis and fibrolysis.





Publication date: Available online 12 April 2018
Source:Matrix Biology

Author(s): William Ramos-Lewis, Andrea Page-McCaw

Basement membrane plays a foundational role in the structure and maintenance of many tissues throughout the animal kingdom. In addition to signaling to cells through cell-surface receptors, basement membrane directly influences the development and maintenance of organ shape via its mechanical properties. The mechanical properties of basement membrane are dictated by its composition, geometry, and crosslinking. Distinguishing between the ways the basement membrane influences morphology in vivo poses a major challenge. Drosophila melanogaster, already established as a powerful model for the analysis of cell signaling, has in recent years emerged as a tractable model for understanding the roles of basement membrane stiffness in vivo, in shaping and maintaining the morphology of tissues and organs. In addition to the plethora of genetic tools available in flies, the major proteins found in vertebrate basement membranes are all present in Drosophila. Furthermore, Drosophila has fewer copies of the genes encoding these proteins, making flies more amenable to genetic manipulation than vertebrate models. Because the development of Drosophila organs has been well-characterized, these different organ systems offer a variety of contexts for analyzing the role of basement membrane in development. The developing egg chamber and central nervous system, for example, have been important models for assessing the role of basement membrane stiffness in influencing organ shape. Studies in the nervous system have also shown how basement membrane stiffness can influence cellular migration in vivo. Finally, work in the imaginal wing disc has illuminated a distinct mechanism by which basement membrane can alter organ shape and size, by sequestering signaling ligands. This mini-review highlights the recent discoveries pertaining to basement membrane mechanics during Drosophila development.





Publication date: Available online 11 April 2018
Source:Matrix Biology

Author(s): Marco Allinovi, Letizia De Chiara, Maria Lucia Angelotti, Francesca Becherucci, Paola Romagnani

Renal fibrosis is a condition characterized by excessive extracellular matrix accumulation in the kidney. Representing the final common result of a variety of injuries, it can lead to chronic kidney disease and end-stage renal disease. Although major efforts have been made in understanding the process of renal fibrosis, attempts to halt its progression have been successful only in a laboratory setting with limited success in clinical practice. Here, we review the current knowledge on the process of renal fibrogenesis and the emerging anti-fibrotic drugs that have shown encouraging results in experimental models and were subsequently tested in clinical trials. We also propose possible explanations that may account for clinical trial failures and poor translation outcomes. Finally, we will discuss alternative therapeutic options and future directions in which anti-fibrotic treatments may be coupled with drugs that can enhance endogenous tissue regeneration.





Publication date: Available online 9 April 2018
Source:Matrix Biology

Author(s): David N. O'Dwyer, Stephen J. Gurczynski, Bethany B. Moore

The lung harbors a complex immune system composed of both innate and adaptive immune cells. Recognition of infection and injury by receptors on lung innate immune cells is crucial for generation of antigen-specific responses by adaptive immune cells. The extracellular matrix of the lung, comprising the interstitium and basement membrane, plays a key role in the regulation of these immune systems. The matrix consists of several hundred assembled proteins that interact to form a bioactive scaffold. This template, modified by enzymes, acts to facilitate cell function and differentiation and changes dynamically with age and lung disease. Herein, we explore relationships between innate and adaptive immunity and the lung extracellular matrix. We discuss the interactions between extracellular matrix proteins, including glycosaminoglycans, with prominent effects on innate immune signaling effectors such as toll-like receptors. We describe the relationship of extracellular matrix proteins with adaptive immunity and leukocyte migration to sites of injury within the lung. Further study of these interactions will lead to greater knowledge of the role of matrix biology in lung immunity. The development of novel therapies for acute and chronic lung disease is dependent on a comprehensive understanding of these complex matrix-immunity interactions.





Publication date: Available online 9 April 2018
Source:Matrix Biology

Author(s): Ying Zhang, Chi Xiong, Mateusz Kudelko, Yan Li, Cheng Wang, Yuk Lun Wong, Vivian Tam, Muhammad Farooq Rai, James Cheverud, Heather A. Lawson, Linda Sandell, Wilson C.W. Chan, Kathryn S.E. Cheah, Pak C. Sham, Danny Chan

Intervertebral disc degeneration (IDD) causes back pain and sciatica, affecting quality of life and resulting in high economic/social burden. The etiology of IDD is not well understood. Along with aging and environmental factors, genetic factors also influence the onset, progression and severity of IDD. Genetic studies of risk factors for IDD using human cohorts are limited by small sample size and low statistical power. Animal models amenable to genetic and functional studies of IDD provide desirable alternatives. Despite differences in size and cellular content as compared to human intervertebral discs (IVDs), the mouse is a powerful model for genetics and assessment of cellular changes relevant to human biology. Here, we provide evidence of early onset disc degeneration in SM/J relative to LG/J mice with poor and good tissue healing capacity respectively. In the first few months of life, LG/J mice maintain a relatively constant pool of notochordal-like cells in the nucleus pulposus (NP) of the IVD. In contrast, chondrogenic events are observed in SM/J mice beginning as early as one-week-old, with progressive fibrotic changes. Further, the extracellular matrix changes in the NP are consistent with IVD degeneration. The proteomic data has been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD008784. Leveraging on the genomic data of two parental and two recombinant inbred lines, we assessed the genetic contribution to the NP changes and identified processes linked to the regulation of ion transport systems. Significantly, “transport” system is also in the top three gene ontology (GO) terms from a comparative proteomic analysis of the mouse NP. SM/J. These findings support the potential of the SM/J, LG/J and the recombinant inbreeds for future genetic and biology in mice and validation of candidate genes and biological relevance in human cohort studies.





Publication date: Available online 9 April 2018
Source:Matrix Biology

Author(s): L. Dupont, G. Ehx, M. Chantry, C. Monseur, C. Leduc, L. Janssen, D. Cataldo, M. Thiry, C. Jerome, J.-M. Thomassin, B. Nusgens, J. Dubail, F. Baron, A. Colige

Since its first description, ADAMTS14 has been considered as an aminoprocollagen peptidase based on its high similarity with ADAMTS3 and ADAMTS2. As its importance for procollagen processing was never experimentally demonstrated in vivo, we generated Adamts14-deficient mice. They are healthy, fertile and display normal aminoprocollagen processing. They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies between these two highly related enzymes. Initial characterizations made on young Adamts2-Adamts14-deficient animals showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils. However, when evaluated at older age, Adamts2-Adamts14-deficient mice surprisingly displayed epidermal lesions, appearing in 2 month-old males and later in some females, and then worsening rapidly. Immunohistological evaluations of skin sections around the lesions revealed thickening of the epidermis, hypercellularity in the dermis and extensive infiltration by immune cells. Additional investigations, performed on young mice before the formation of the initial lesions, revealed that the primary cause of the phenotype was not related to alterations of the epidermal barrier but was rather the result of an abnormal activation and differentiation of T lymphocytes towards a Th1 profile. However, the primary molecular defect probably does not reside in the immune system itself since irradiated Adamts2-Adamts14-deficient mice grafted with WT immune cells still developed lesions. While originally created to better characterize the common and specific functions of ADAMTS2 and ADAMTS14 in extracellular matrix and connective tissues homeostasis, the Adamts2-Adamts14-deficient mice revealed an unexpected but significant role of ADAMTS in the regulation of immune system, possibly through a cross-talk involving mesenchymal cells and the TGFβ pathways.





Publication date: Available online 5 April 2018
Source:Matrix Biology

Author(s): Cristina Has, Alexander Nyström, Amir Hossain Saeidian, Leena Bruckner-Tuderman, Jouni Uitto

Epidermolysis bullosa (EB), a group of heritable skin fragility disorders, is characterized by blistering, erosions and chronic ulcers in the skin and mucous membranes. In some forms, the blistering phenotype is associated with extensive mutilating scarring and development of aggressive squamous cell carcinomas. The skin findings can be associated with extracutaneous manifestations in the ocular as well as gastrointestinal and vesico-urinary tracts. The phenotypic heterogeneity reflects the presence of mutations in as many as 20 different genes expressed in the cutaneous basement membrane zone, and the types and combinations of the mutations and their consequences at the mRNA and protein levels contribute to the spectrum of severity encountered in different subtypes of EB. This overview highlights the molecular genetics of EB based on mutations in the genes encoding type VII and XVII collagens as well as laminin-332. The mutations identified in these protein components of the extracellular matrix attest to their critical importance in providing stability to the cutaneous basement membrane zone, with implications for heritable and acquired diseases.





Publication date: Available online 4 April 2018
Source:Matrix Biology

Author(s): Nadine Nagy, Hedwich F. Kuipers, Payton L. Marshall, Esther Wang, Gernot Kaber, Paul L. Bollyky

The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity.





Publication date: Available online 3 April 2018
Source:Matrix Biology

Author(s): Renato V. Iozzo, Maria A. Gubbiotti

Like the major theme of a Mozart concerto, the immense and pervasive extracellular matrix drives each movement and ultimately closes the symphony, embracing a unique role as the fundamental mediator for most, if not all, ensuing intracellular events. As such, it comes as no surprise that the mechanism of just about every known disease can be traced back to some part of the matrix, typically in the form of an abnormal amount or activity level of a particular matrix component. These defects considerably affect downstream signaling axes leading to overt cellular dysfunction, organ failure, and death. From skin to bone, from vessels to brain, from eyes to all the internal organs, the matrix plays an incredible role as both a cause and potential means to reverse diseases. Human malaises including connective tissue disorders, muscular dystrophy, fibrosis, and cancer are all extracellular matrix-driven diseases. The ability to understand and modulate these matrix-related mechanisms may lead to the future discovery of novel therapeutic options for these patients.





Publication date: Available online 3 April 2018
Source:Matrix Biology

Author(s): Justin C. Hewlett, Jonathan A. Kropski, Timothy S. Blackwell

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disease of the lung that is marked by progressive decline in pulmonary function and ultimately respiratory failure. Genetic and environmental risk factors have been identified that indicate injury to, and dysfunction of the lung epithelium is central to initiating the pathogenic process. Following injury to the lung epithelium, growth factors, matrikines and extracellular matrix driven signaling together activate a variety of repair pathways that lead to inflammatory cell recruitment, fibroblast proliferation and expansion of the extracellular matrix, culminating in tissue fibrosis. This tissue fibrosis then leads to changes in the biochemical and biomechanical properties of the extracellular matrix, which potentiate profibrotic mechanisms through a “feed-forward cycle.” This review provides an overview of the interactions of the pathogenic mechanisms of IPF with a focus on epithelial-mesenchymal crosstalk and the extracellular matrix as a therapeutic target for idiopathic pulmonary fibrosis.





Publication date: Available online 29 March 2018
Source:Matrix Biology

Author(s): Eva Brauchle, Jana Kasper, Ruben Daum, Nicolas Schierbaum, Claudius Falch, Andreas Kirschniak, Tilman E. Schäffer, Katja Schenke-Layland

The extracellular matrix (ECM) is extensively remodeled in tumor tissues. Overproduction of collagens, pathological collagen crosslinking and alignment of fibers are major processes that ultimately result in an increased tissue stiffness. Although it is known that glycosaminoglycans (GAGs) play an important role in tumor signaling, their contribution to the biomechanical properties of tumor ECM is unknown. In this study, ECM structures of human colon carcinoma and normal (control) colon tissues were histologically identified. Using atomic force microscopy (AFM) nanoindentation, we show that the collagen-rich regions within the ECM of colon carcinoma tissues were significantly stiffer than the submucosal collagen-rich layer of control tissues. Screening of these regions with Raman microspectroscopy revealed significantly different molecular fingerprints for collagen fibers in colon carcinoma tissues compared to control tissues. We further showed an increased alignment of collagen fibers and elevated levels of GAG immuno-reactivity within the collagen network of colon carcinoma tissues. GAGs such as heparan sulfate and chondroitin sulfate were detected in significantly elevated levels in collagen fibers of carcinoma tissues. Moreover, immunodetection of the collagen-associated proteoglycan decorin was significantly decreased in carcinomas tissues of individual patients when compared with the corresponding control tissues. Overall a strong patient-to-patient variability was evident in the ECM composition, structure and biomechanics of individual colon carcinoma tissues. Although, biomechanical characteristics of tumor ECM were not directly impacted by GAG content, GAGs might play an important role during the mechanical and structural remodeling of pathological tumor ECM. To manipulate GAG expression and deposition in tumor microenvironments could represent a novel potential therapeutic strategy.





Publication date: Available online 29 March 2018
Source:Matrix Biology

Author(s): Hyowon Choi, Steven Tessier, Elizabeth S. Silagi, Rutvin Kyada, Farzad Yousefi, Nancy Pleshko, Irving M. Shapiro, Makarand V. Risbud

Intervertebral disc degeneration and associated low back and neck pain is a ubiquitous health condition that affects millions of people world-wide, and causes high incidence of disability and enormous medical/societal costs. However, lack of appropriate small animal models with spontaneous disease onset has impeded our ability to understand the pathogenetic mechanisms that characterize and drive the degenerative process. We report, for the first time, early onset spontaneous disc degeneration in SM/J mice known for their poor regenerative capacities compared to “super-healer” LG/J mice. In SM/J mice, degenerative process was marked by decreased nucleus pulposus (NP) cellularity and changes in matrix composition at P7, 4, and 8 weeks with increased severity by 17 weeks. Distinctions between NP and annulus fibrosus (AF) or endplate cartilage were lost, and NP and AF of SM/J mice showed higher histological grades. There was increased NP cell death in SM/J mice with decreased phenotypic marker expression. Polarized microscopy and FTIR spectroscopy demonstrated replacement of glycosaminoglycan-rich NP matrix with collagenous fibrous tissue. The levels of ARGxx were increased in, indicating higher aggrecan turnover. Furthermore, an aberrant expression of collagen X and MMP13 was observed in the NP of SM/J mice, along with elevated expression of Col10a1, Ctgf, and Runx2, markers of chondrocyte hypertrophy. Likewise, expression of Enpp1 as well as Alpl was higher, suggesting NP cells of SM/J mice promote dystrophic mineralization. There was also a decrease in several pathways necessary for NP cell survival and function including Wnt and VEGF signaling. Importantly, SM/J discs were stiffer, had decreased height, and poor vertebral bone quality, suggesting compromised motion segment mechanical functionality. Taken together, our results clearly demonstrate that SM/J mouse strain recapitulates many salient features of human disc degeneration, and serves as a novel small animal model.





Publication date: Available online 27 March 2018
Source:Matrix Biology

Author(s): Kristmundur Sigmundsson, Juha R.M. Ojala, Miina K. Öhman, Anne-May Österholm, Aida Moreno-Moral, Anna Domogatskaya, Li Yen Chong, Yang Sun, Xiaoran Chai, Joseph A.M. Steele, Benjamin George, Manuel Patarroyo, Ann-Sofie Nilsson, Sergey Rodin, Sujoy Ghosh, Molly M. Stevens, Enrico Petretto, Karl Tryggvason

The efficacy of islet transplantation for diabetes treatment suffers from lack of cadaver-derived islets, islet necrosis and long transfer times prior to transplantation. Here, we developed a method for culturing mouse and human islets in vitro on α5-laminins, which are natural components of islet basement membranes. Adhering islets spread to form layers of 1–3 cells in thickness and remained normoxic and functional for at least 7 days in culture. In contrast, spherical islets kept in suspension developed hypoxia and central necrosis within 16 h. Transplantation of 110–150 mouse islets cultured on α5-laminin-coated polydimethylsiloxane membranes for 3–7 days normalized blood glucose already within 3 days in mice with streptozotocin-induced diabetes. RNA-sequencing of isolated and cultured mouse islets provided further evidence for the adhesion and spreading achieved with α5-laminin. Our results suggest that use of such in vitro expanded islets may significantly enhance the efficacy of islet transplantation treatment for diabetes.





Publication date: Available online 27 March 2018
Source:Matrix Biology

Author(s): Yu Yamaguchi, Hayato Yamamoto, Yuki Tobisawa, Fumitoshi Irie

Hyaluronan (HA) is a glycosaminoglycan (GAG) composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. HA is an extremely long, unbranched polymer, which often exceeds 106 Da and sometimes reaches 107 Da. A feature that epitomizes HA is its rapid turnover; one-third of the total body HA is turned over daily. The current model of HA catabolism postulates that high-molecular weight HA in the extracellular space is first cleaved into smaller fragments by a hyaluronidase(s) that resides at the cell surface, followed by internalization of fragments and their degradation into monosaccharides in lysosomes. Over the last decade, considerable research has shown that the HYAL family of hyaluronidases plays significant roles in HA catabolism. Nonetheless, the identity of a hyaluronidase responsible for the initial step of HA cleavage on the cell surface remains elusive, as biochemical and enzymological properties of HYAL proteins are not entirely consistent with those expected of cell surface hyaluronidases. Recent identification of transmembrane 2 (TMEM2) as a cell surface protein that possesses potent hyaluronidase activity suggests that it may be the “missing” cell surface hyaluronidase, and that novel models of HA catabolism should include this protein.





Publication date: Available online 23 March 2018
Source:Matrix Biology

Author(s): Sina A. Gharib, Anne M. Manicone, William C. Parks

Several studies have implicated a causative role for specific matrix metalloproteinases (MMPs) in the development and progression of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) and its severe sequela, emphysema. However, the precise function of any given MMP in emphysema remains an unanswered question. Emphysema results from the degradation of alveolar elastin – among other possible mechanisms – a process that is often thought to be caused by elastolytic proteinases made by macrophages. In this article, we discuss the data suggesting, supporting, or refuting causative roles of macrophage-derived MMPs, with a focus on MMPs-7, -9, -10, -12, and 28, in both the human disease and mouse models of emphysema. Findings from experimental models suggest that some MMPs, such as MMP-12, may directly breakdown elastin, whereas others, particularly MMP-10 and MMP-28, promote the development of emphysema by influencing the proteolytic and inflammatory activities of macrophages.





Publication date: Available online 21 March 2018
Source:Matrix Biology

Author(s): Aaron C. Petrey, Carol A. de la Motte

Hyaluronan, a major extracellular matrix component, is an active participant in many disease states, including inflammatory bowel disease (IBD). The synthesis of this dynamic polymer is increased at sites of inflammation. Hyaluronan together with the enzymes responsible for its synthesis, degradation, and its binding proteins, directly modulates the promotion and resolution of disease by controlling recruitment of immune cells, by release of inflammatory cytokines, and by balancing hemostasis. This review discusses the functional significance of hyaluronan in the cells and tissues involved in inflammatory bowel disease pathobiology.





Publication date: Available online 21 March 2018
Source:Matrix Biology

Author(s): Yasaman Ramazani, Noël Knops, Mohamed A. Elmonem, Tri Q. Nguyen, Fanny Oliveira Arcolino, Lambert van den Heuvel, Elena Levtchenko, Dirk Kuypers, Roel Goldschmeding

Connective tissue growth factor, also known as CCN2, is a cysteine-rich matricellular protein involved in the control of biological processes, such as cell proliferation, differentiation, adhesion and angiogenesis, as well as multiple pathologies, such as tumor development and tissue fibrosis. Here, we describe the molecular and biological characteristics of CTGF, its regulation and various functions in the spectrum of development and regeneration to fibrosis. We further outline the preclinical and clinical studies concerning compounds targeting CTGF in various pathologies with the focus on heart, lung, liver, kidney and solid organ transplantation. Finally, we address the advances and pitfalls of translational fibrosis research and provide suggestions to move towards a better management of fibrosis.





Publication date: Available online 20 March 2018
Source:Matrix Biology

Author(s): Olivier Burgy, Melanie Königshoff

The WNT signaling pathways are major regulators of organ development. Ample research over the past decades further revealed that these pathways are critically involved in adult tissue homeostasis and stem cell function as well as the development of chronic diseases, such as cancer and fibrosis. In this review, we will describe the different WNT signal pathways, summarize the current evidence of WNT signal involvement in wound healing and fibrosis, and highlight potential novel therapeutic options for fibrotic disorders targeting WNT signaling pathways.





Publication date: Available online 20 March 2018
Source:Matrix Biology

Author(s): Chia-yi Chen, Esther Melo, Peter Jakob, Arno Friedlein, Brigitta Elsässer, Peter Goettig, Verena Kueppers, Frederic Delobel, Corinne Stucki, Tom Dunkley, Sascha Fauser, Oliver Schilling, Roberto Iacone

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population. Variants in the HTRA1-ARMS2 locus have been linked to increased AMD risk. In the present study we investigated the impact of elevated HtrA1 levels on the retina pigment epithelial (RPE) secretome using a polarized culture system. Upregulation of HtrA1 alters the abundance of key proteins involved in angiogenesis and extracellular matrix remodeling. Thrombospondin-1, an angiogenesis modulator, was identified as a substrate for HtrA1 using terminal amine isotope labeling of substrates in conjunction with HtrA1 specificity profiling. HtrA1 cleavage of thrombospondin-1 was further corroborated by in vitro cleavage assays and targeted proteomics together with small molecule inhibition of HtrA1. While thrombospondin-1 is anti-angiogenic, the proteolytically released N-terminal fragment promotes the formation of tube-like structure by endothelial cells. Taken together, our findings suggest a mechanism by which increased levels of HtrA1 may contribute to AMD pathogenesis. The proteomic data has been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier. For quantitative secretome analysis, project accession: PXD007691, username: reviewer45093@ebi.ac.uk, password: 1FUpS6Yq. For TAILS analysis, project accession: PXD007139, username: reviewer76731@ebi.ac.uk, password: sNbMp7xK.





Publication date: Available online 19 March 2018
Source:Matrix Biology

Author(s): Ankita Burman, Harikrishna Tanjore, Timothy S. Blackwell

Endoplasmic reticulum (ER) stress is associated with development and progression of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). ER stress was first implicated in the pathogenesis of IPF >15 years ago with the discovery of disease-causing mutations in surfactant protein C, which result in a misfolded gene product in type II alveolar epithelial cells (AECs). ER stress and the unfolded protein response (UPR) have been linked to lung fibrosis through regulation of AEC apoptosis, epithelial-mesenchymal transition, myofibroblast differentiation, and M2 macrophage polarization. Although progress has been made in understanding the causes and consequences of ER stress in IPF and a number of chronic fibrotic disorders, further studies are needed to identify key factors that induce ER stress in important cell types and define critical down-stream processes and effector molecules that mediate ER stress-related phenotypes. This review discusses potential causes of ER stress induction in the lungs and current evidence linking ER stress to fibrosis in the context of individual cell types: AECs, fibroblasts, and macrophages. As our understanding of the relationship between ER stress and lung fibrosis continues to evolve, future studies will examine new strategies to modulate UPR pathways for therapeutic benefit.





Publication date: Available online 19 March 2018
Source:Matrix Biology

Author(s): Guoying Yu, Gabriel H. Ibarra, Naftali Kaminski

In recent decades there has been a significant shift in our understanding of idiopathic pulmonary fibrosis (IPF), a progressive and lethal disorder. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models of disease, in recent decades new insights derived from humans with IPF have taken precedence. This is mainly because of the establishment of large collections of IPF lung tissues and patient cohorts, and the emergence of high throughput profiling technologies collectively termed ‘omics’ technologies based on their shared suffix. In this review we describe impacts of ‘omics’ analyses of human IPF samples on our understanding of the disease. In particular, we discuss the results of genomics and transcriptomics studies, as well as proteomics, epigenomics and metabolomics. We then describe how these findings can be integrated in a modified paradigm of human idiopathic pulmonary fibrosis, that introduces the ‘hallmarks of aging’ as a central theme in the IPF lung. This allows resolution of all the disparate cellular and molecular features in IPF, from the central role of epithelial cells, through the dramatic phenotypic alterations observed in fibroblasts and the numerous aberrations that inflammatory cells exhibit. We end with reiterating a call for renewed efforts to collect and analyze carefully characterized human tissues, in ways that would facilitate implementation of novel technologies for high resolution single cell omics profiling.





Publication date: Available online 17 March 2018
Source:Matrix Biology

Author(s): Bon-Hee Gu, Matthew C. Madison, David Corry, Farrah Kheradmand

Multicellular organisms synthesize and renew components of their subcellular and scaffolding proteins, collectively known as the extracellular matrix molecules (ECMs). In the lung, ECMs maintain tensile strength, elasticity, and dictate the specialized function of multiple cell lineages. These functions are critical in lung homeostatic processes including cellular migration and proliferation during morphogenesis or in response to repair. Alterations in lung ECMs that expose cells to new cryptic fragments, generated in response to endogenous proteinases or exogenous toxins, are associated with the development of several common respiratory diseases. How lung ECMs provide or relay vital signals to epithelial and mesenchymal cells has shed new light on development and progression of several common chronic respiratory diseases. This review will consider how ECMs regulate lung homeostasis and their reorganization under pathological conditions that can modulate the inflammatory diseases asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Better understanding of changes in the distribution of lung ECM could provide novel therapeutic approaches to treat chronic lung diseases.





Publication date: Available online 15 March 2018
Source:Matrix Biology

Author(s): Sanne D'hondt, Brecht Guillemyn, Delfien Syx, Sofie Symoens, Riet De Rycke, Leen Vanhoutte, Wendy Toussaint, Bart N. Lambrecht, Anne De Paepe, Douglas R. Keene, Yoshihiro Ishikawa, Hans Peter Bächinger, Sophie Janssens, Mathieu J.M. Bertrand, Fransiska Malfait

Type III collagen is a major fibrillar collagen consisting of three identical α1(III)-chains that is particularly present in tissues exhibiting elastic properties, such as the skin and the arterial wall. Heterozygous mutations in the COL3A1 gene result in vascular Ehlers-Danlos syndrome (vEDS), a severe, life-threatening disorder, characterized by thin, translucent skin and propensity to arterial, intestinal and uterine rupture. Most human vEDS cases result from a missense mutation substituting a crucial glycine residue in the triple helical domain of the α1(III)-chains. The mechanisms by which these mutant type III collagen molecules cause dermal and vascular fragility are not well understood. We generated a transgenic mouse line expressing mutant type III collagen, containing a typical helical glycine substitution (p.(Gly182Ser)). This Col3a1 Tg-G182S mouse line displays a phenotype recapitulating characteristics of human vEDS patients with signs of dermal and vascular fragility. The Col3a1 Tg-G182S mice develop severe transdermal skin wounds, resulting in early demise at 13–14weeks of age. We found that this phenotype was associated with a reduced total collagen content and an abnormal collagen III:I ratio, leading to the production of severely malformed collagen fibrils in the extracellular matrix of dermal and arterial tissues. These results indicate that expression of the glycine substitution in the α1(III)-chain disturbs formation of heterotypic type III:I collagen fibrils, and thereby demonstrate a key role for type III collagen in collagen fibrillogenesis in dermal and arterial tissues.





Publication date: Available online 12 March 2018
Source:Matrix Biology

Author(s): Kinga I. Gawlik, Vahid M. Harandi, Rachel Y. Cheong, Åsa Petersén, Madeleine Durbeej

Muscular dystrophies, including laminin α2 chain-deficient muscular dystrophy (LAMA2-CMD), are associated with immense personal, social and economic burdens. Thus, effective treatments are urgently needed. LAMA2-CMD is either a severe, early-onset condition with complete laminin α2 chain-deficiency or a milder, late-onset form with partial laminin α2 chain-deficiency. Mouse models dy 3K /dy 3K and dy 2J /dy 2J , respectively, recapitulate these two forms of LAMA2-CMD very well. We have previously demonstrated that laminin α1 chain significantly reduces muscular dystrophy in laminin α2 chain-deficient dy 3K /dy 3K mice. Among all the different pre-clinical approaches that have been evaluated in mice, laminin α1 chain-mediated therapy has been shown to be one of the most effective lines of attack. However, it has remained unclear if laminin α1 chain-mediated treatment is also applicable for partial laminin α2 chain-deficiency. Hence, we have generated dy 2J /dy 2J mice (that express a substantial amount of an N-terminal truncated laminin α2 chain) overexpressing laminin α1 chain in the neuromuscular system. The laminin α1 chain transgene ameliorated the dystrophic phenotype, restored muscle strength and reduced peripheral neuropathy. Thus, these findings provide additional support for the development of laminin α1 chain-based therapy for LAMA2-CMD.





Publication date: Available online 11 March 2018
Source:Matrix Biology

Author(s): Roy Morello

Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.





Publication date: Available online 9 March 2018
Source:Matrix Biology

Author(s): Karen L. Posey, Francoise Coustry, Jacqueline T. Hecht

Cartilage oligomeric matrix protein (COMP) is a large pentameric glycoprotein that interacts with multiple extracellular matrix proteins in cartilage and other tissues. While, COMP is known to play a role in collagen secretion and fibrillogenesis, chondrocyte proliferation and mechanical strength of tendons, the complete range of COMP functions remains to be defined. COMPopathies describe pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), two skeletal dysplasias caused by autosomal dominant COMP mutations. The majority of the mutations are in the calcium binding domains and compromise protein folding. COMPopathies are ER storage disorders in which the retention of COMP in the chondrocyte ER stimulates overwhelming cellular stress. The retention causes oxidative and inflammation processes leading to chondrocyte death and loss of long bone growth. In contrast, dysregulation of wild-type COMP expression is found in numerous diseases including: fibrosis, cardiomyopathy and breast and prostate cancers. The most exciting clinical application is the use of COMP as a biomarker for idiopathic pulmonary fibrosis and cartilage degeneration associated osteoarthritis and rheumatoid and, as a prognostic marker for joint injury. The ever expanding roles of COMP in single gene disorders and multifactorial diseases will lead to a better understanding of its functions in ECM and tissue homeostasis towards the goal of developing new therapeutic avenues.





Publication date: Available online 9 March 2018
Source:Matrix Biology

Author(s): Huimin Lu, Nicholas Bowler, Larry A. Harshyne, D. Craig Hooper, Shiv Ram Krishn, Senem Kurtoglu, Carmine Fedele, Qin Liu, Hsin-Yao Tang, Andrew V. Kossenkov, William K. Kelly, Kerith Wang, Rhonda B. Kean, Paul H. Weinreb, Lei Yu, Anindita Dutta, Paolo Fortina, Adam Ertel, Maria Stanczak, Flemming Forsberg, Dmitry I. Gabrilovich, David W. Speicher, Dario C. Altieri, Lucia R. Languino

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvβ6 is transferred from cancer cells to monocytes, including β6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvβ6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvβ6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvβ6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Pten pc−/− prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvβ6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvβ6 from cancer cells to monocytes through exosomes.





Publication date: Available online 8 March 2018
Source:Matrix Biology

Author(s): Yong Zhou, Jeffrey C. Horowitz, Alexandra Naba, Namasivayam Ambalavanan, Kamran Atabai, Jenna Balestrini, Peter B. Bitterman, Richard A. Corley, Bi-Sen Ding, Adam J. Engler, Kirk C. Hansen, James S. Hagood, Farrah Kheradmand, Qing S. Lin, Enid Neptune, Laura Niklason, Luis A. Ortiz, William C. Parks, Daniel J. Tschumperlin, Eric S. White, Harold A. Chapman, Victor J. Thannickal

The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.





Publication date: Available online 7 March 2018
Source:Matrix Biology

Author(s): Clarissa S. Craft, Thomas J. Broekelmann, Robert P. Mecham

Microfibril-associated glycoproteins 1 and 2 (MAGP-1, MAGP-2) are protein components of extracellular matrix microfibrils. These proteins interact with fibrillin, the core component of microfibrils, and impart unique biological properties that influence microfibril function in vertebrates. MAGPs bind active forms of TGFβ and BMPs and are capable of modulating Notch signaling. Mutations in MAGP-1 or MAGP-2 have been linked to thoracic aneurysms and metabolic disease in humans. MAGP-2 has also been shown to be an important biomarker in several human cancers. Mice lacking MAGP-1 or MAGP-2 have defects in multiple organ systems, which reflects the widespread distribution of microfibrils in vertebrate tissues. This review summarizes our current understanding of the function of the MAGPs and their relationship to human disease.





Publication date: Available online 6 March 2018
Source:Matrix Biology

Author(s): Awen Menou, JanWillem Duitman, Bruno Crestani

Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evidence indicates that Protease-Activated Receptors (PARs) inhibition in IPF may be promising for future evaluation. Therefore, proteases and anti-proteases aroused great biomedical interest over the past years, owing to the identification of their potential roles in lung fibrosis. During these last decades, numerous other proteases and anti-proteases have been studied in lung fibrosis, such as matriptase, Human airway trypsin-like protease (HAT), Hepatocyte growth factor activator (HGFA)/HGFA activator inhibitor (HAI) system, Plasminogen activator inhibitor (PAI)-1, Protease nexine (PN)-1, cathepsins, calpains, and cystatin C. Herein, we provide a general overview of the proteases and anti-proteases unbalance during lung fibrogenesis and explore potential therapeutics for IPF.





Publication date: Available online 6 March 2018
Source:Matrix Biology

Author(s): M. Forouhan, K. Mori, R.P. Boot-Handford

Whilst the role of ATF6α in modulating the unfolded protein response (UPR) has been well documented, the function of its paralogue ATF6β is less well understood. Using knockdown in cell culture and gene ablation in mice we have directly compared the roles of ATF6α & β in responding to the increased ER stress induced by mutant forms of type X collagen that cause the ER stress-associated metaphyseal chondrodysplasia type Schmid (MCDS). ATF6α more efficiently deals with the disease-associated ER stress in the absence of ATF6β and conversely, ATF6β is less effective in the absence of ATF6α. Furthermore, disease severity in vivo is increased by ATF6α ablation and decreased by ATF6β ablation. In addition, novel functions for each paralogue are described including an ATF6β-specific role in controlling growth plate chondrocyte proliferation. The clear demonstration of the intimate relationship of the two ATF6 isoforms and how ATF6β can moderate the activity of ATF6α and vice versa is of great significance for understanding the UPR mechanism. The activities of both ATF6 isoforms and their separate roles need consideration when deciding how to target increased ER stress as a means of treating MCDS and other ER stress-associated diseases.





Publication date: Available online 5 March 2018
Source:Matrix Biology

Author(s): S.E. Turecamo, T.A. Walji, T.J. Broekelmann, J.W. Williams, S. Ivanov, N.K. Wee, J.D. Procknow, M.R. McManus, G.J. Randolph, E.L. Scheller, R.P. Mecham, C.S. Craft

Microfibril-associated glycoprotein-1 (MAGP1) is an extracellular matrix protein that interacts with fibrillin and is involved in regulating the bioavailability of signaling molecules such as TGFβ. Mice with germline MAGP1 deficiency (Mfap2 −/− ) develop increased adiposity, hyperglycemia, insulin resistance, bone marrow adipose tissue expansion, reduced cancellous bone mass, cortical bone thinning and bone fragility. The goal of this study was to assess whether the Mfap2 −/− bone phenotypes were due to loss of MAGP1 locally or secondary to a change in whole body physiology (metabolic dysfunction). To do this, mice with conditional deletion of MAGP1 in the limb skeleton were generated by crossing MAGP1-flox mice (Mfap2 lox/lox ) with Prx1-Cre mice. Mfap2 Prx−/− mice did not show any changes in peripheral adiposity, hyperglycemia or insulin sensitivity, but did have increased bone length and cancellous bone loss that was comparable to the germline Mfap2 −/− knockout. Unlike the germline knockout, marrow adiposity, cortical bone thickness and bone strength in Mfap2 Prx−/− mice were normal. These findings implicate systemic metabolic dysfunction in the development of bone fragility in germline Mfap2 −/− mice. An unexpected finding of this study was the detection of MAGP1 protein in the Mfap2 Prx−/− hematopoietic bone marrow, despite the absence of MAGP1 protein in osseous bone matrix and absent Mfap2 transcript expression at both sites. This suggests MAGP1 from a secondary site may accumulate in the bone marrow, but not be incorporated into the bone matrix, during times of regional MAGP1 depletion.





Publication date: Available online 3 March 2018
Source:Matrix Biology

Author(s): Jens W. Fischer

Hyaluronan (HA), HA synthases (HAS) and HA receptors are expressed during the progression of atherosclerotic plaques. HA is thought to promote the activated phenotype of local vascular smooth muscle cells characterized by increased migration, proliferation and matrix synthesis. Furthermore, HA may modulate the immune response by increasing macrophage retention and by promoting the polarization of Th1 cells that enhance macrophage driven inflammation as well. The pro-atherosclerotic functions of HA are opposed by the presence of HA in the glycocalyx where it critically contributes to anti-thrombotic and anti-inflammatory function of the glycocalyx. Patients with atherosclerosis often are affected by comorbidities among them diabetes mellitus type 2 and inflammatory comorbidities. Diabetes mellitus type 2 likely has close interrelations to HA synthesis in atherosclerosis because the activity and transcription of HA synthases are sensitive to the intracellular glucose metabolism, which determines the substrate availability and the posttranslational modifications of HA synthases. The pro-inflammatory comorbidities aggravate the course of atherosclerosis and will affect the expression of the genes related to HA biosynthesis, -degradation, HA-matrix assembly or signaling. One example being the induction of HAS3 by interleukin-1β and other cytokines. Furthermore complications of atherosclerosis such as the healing after myocardial infarction also involve HA responses.





Publication date: Available online 3 March 2018
Source:Matrix Biology

Author(s): Karen K. McKee, Maya Aleksandrova, Peter D. Yurchenco

Laminin polymerization is a key step of basement membrane self-assembly that depends on the binding of the three different N-terminal globular LN domains. Several mutations in the LN domains cause LAMA2-deficient muscular dystrophy and LAMB2-deficient Pierson syndrome. These mutations may affect polymerization. A novel approach to identify the amino acid residues required for polymerization has been applied to an analysis of these and other laminin LN mutations. The approach utilizes laminin-nidogen chimeric fusion proteins that bind to recombinant non-polymerizing laminins to provide a missing functional LN domain. Single amino acid substitutions introduced into these chimeras were tested to determine if polymerization activity and the ability to assemble on cell surfaces were lost. Several laminin-deficient muscular dystrophy mutations, renal Pierson syndrome mutations, and Drosophila mutations causing defects of heart development were identified as ones causing loss of laminin polymerization. In addition, two novel residues required for polymerization were identified in the laminin γ1 LN domain.





Publication date: Available online 3 March 2018
Source:Matrix Biology

Author(s): Mala Mahendroo

Cervical hyaluronan (HA) synthesis is robustly induced in late pregnancy in numerous species including women and mice. Recent evidence highlights the diverse and dynamic functions of HA in cervical biology that stem from its expression in the cervical stroma, epithelia and immune cells, changes in HA molecular weight and cell specific expression of HA binding partners. Mice deficient in HA in the lower reproductive tract confirm a structural role of HA to increase spacing and disorganization of fibrillar collagen, though this function is not critical for pregnancy and parturition. In addition, cervical HA depletion via targeted deletion of HA synthase genes, disrupts cell signaling required for the differentiation of epithelia and their mucosal and junctional barrier, resulting in increased susceptibility to ascending infection-mediated preterm birth. Finally the generation of HA disaccharides by bacterial hyaluronidases as made by Group B streptococcus can ligate toll like receptors TLR2/4 thus preventing appropriate inflammatory responses as needed to fight ascending infection and preterm birth. This review summarizes our current understanding of HA's novel and unique roles in cervical remodeling in the process of birth.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Melanie C. Föll, Matthias Fahrner, Christine Gretzmeier, Käthe Thoma, Martin L. Biniossek, Dimitra Kiritsi, Frank Meiss, Oliver Schilling, Alexander Nyström, Johannes S. Kern

In this study we used a genetic extracellular matrix (ECM) disease to identify mechanisms associated with aggressive behavior of cutaneous squamous cell carcinoma (cSCC). cSCC is one of the most common malignancies and usually has a good prognosis. However, some cSCCs recur or metastasize and cause significant morbidity and mortality. Known factors that are associated with aggressiveness of cSCCs include tumor grading, size, localization and microinvasive behavior. To investigate molecular mechanisms that influence biologic behavior we used global proteomic and histologic analyses of formalin-fixed paraffin-embedded tissue of primary human cSCCs. We compared three groups: non-recurring, non-metastasizing low-risk sporadic cSCCs; metastasizing sporadic cSCCs; and cSCCs from patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a genetic skin blistering and ECM disease caused by collagen VII deficiency. Patients commonly suffer from high-risk early onset cSCCs that frequently metastasize. The results indicate that different processes are associated with formation of RDEB cSCCs compared to sporadic cSCCs. Sporadic cSCCs show signs of UV damage, whereas RDEB cSCCs have higher mutational rates and display tissue damage, inflammation and subsequent remodeling of the dermal ECM as tumor initiating factors. Interestingly the two high-risk groups – high-risk metastasizing sporadic cSCCs and RDEB cSCCs – are both associated with tissue damage and ECM remodeling in gene-ontology enrichment and Search Tool for the Retrieval of Interacting Genes/Proteins analyses. In situ histologic analyses validate these results. The high-risk cSCCs also show signatures of enhanced bacterial challenge. Histologic analyses confirm correlation of bacterial colonization with worse prognosis. Collectively, this unbiased study – performed directly on human patient material – reveals that common microenvironmental alterations linked to ECM remodeling and increased bacterial challenges are denominators of high-risk cSCCs. The proteins identified here could serve as potential diagnostic markers and therapeutic targets in high-risk cSCCs.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Hassan Vahidnezhad, Leila Youssefian, Amir Hossein Saeidian, Hamidreza Mahmoudi, Andrew Touati, Maryam Abiri, Abdol-Mohammad Kajbafzadeh, Sophia Aristodemou, Lu Liu, John A. McGrath, Adam Ertel, Eric Londin, Ariana Kariminejad, Sirous Zeinali, Paolo Fortina, Jouni Uitto

Epidermolysis bullosa (EB) is caused by mutations in as many as 19 distinct genes. We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction. The NGS panel was applied to a cohort of 92 consanguineous families of unknown subtype of EB. In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids. Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151. Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis. Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures. The patient also had history of nephropathy with proteinuria. Collectively, the results suggest that biallelic loss-of-function mutations in CD151 underlie an autosomal recessive mechano-bullous disease with systemic features. Thus, CD151 should be considered as the 20th causative, EB-associated gene.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Olena Molokanova, Kai Schönig, Shih-Yen Weng, Xiaoyu Wang, Matthias Bros, Mustafa Diken, Svetlana Ohngemach, Morten Karsdal, Dennis Strand, Alexei Nikolaev, Leonid Eshkind, Detlef Schuppan

Organ fibrosis is characterized by a chronic wound-healing response, with excess deposition of extracellular matrix components. Here, collagen type I represents the most abundant scar component and a primary target for antifibrotic therapies. Liver fibrosis can progress to cirrhosis and primary liver cancer, which are the major causes of liver related morbidity and mortality. However, a (pro-)collagen type I specific therapy remains difficult and its therapeutic abrogation may incur unwanted side effects. We therefore designed tetracycline-regulated procollagen alpha1(I) short hairpin (sh)RNA expressing mice that permit a highly efficient inducible knockdown of the procollagen alpha1(I) gene in activated (myo-)fibroblasts, to study the effect of induced procollagen type I deficiency. Transgenic mice were generated using recombinase-mediated integration in embryonic stem cells or zinc-finger nuclease-aided genomic targeting combined with miR30-shRNA technology. Liver fibrosis was induced in transgenic mice by carbon tetrachloride, either without or with doxycycline supplementation. Doxycycline treated mice showed an 80–90% suppression of procollagen alpha1(I) transcription and a 40–50% reduction in hepatic collagen accumulation. Procollagen alpha1(I) knockdown also downregulated procollagens type III, IV and VI and other fibrosis related parameters. Moreover, this was associated with an attenuation of chronic inflammation, suggesting that collagen type I serves not only as major scar component, but also as modulator of other collagens and promoter of chronic inflammation.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Alessandra Capuano, Federico Fogolari, Francesco Bucciotti, Paola Spessotto, Pier Andrea Nicolosi, Maria Teresa Mucignat, Marta Cervi, Gennaro Esposito, Alfonso Colombatti, Roberto Doliana

EMILIN1, a homo-trimeric adhesive ECM glycoprotein, interacts with the α4β1 integrin through its gC1q domain. Uniquely among the C1q family members, the EMILIN1 gC1q presents only nine-stranded β-sandwich fold and the missing strand is substituted by a disordered 19-residue long segment spanning from Y927 to G945 at the apex of the gC1q domain. This unstructured loop exposes to the solvent the acidic residue E933, which plays a key role in the α4β1 integrin mediated interaction. Here, we experimentally determined that the three E933 residues (one from each monomer) are all required for ligand binding. By docking the NMR structure of the gC1q to a virtual α4β1 crystal structure based on the known structures of α4β7 and α5β1 integrins we built a model of α4β1-gC1q complex where three E933 residues are smoothly forced to coordinate the Mg2+ ion at the βI MIDAS site of the integrin. By bringing the three E933 close in space, the trimeric supramolecular organization of gC1q allows the formation of a proper 3D geometry and suggests a quaternary-structure-dependent mode of interaction. Furthermore, we experimentally identified R904 as a synergistic residue for cell adhesion. Accordingly, the model showed that this residue is able to form potential stabilizing intra-chain salt bridges with residues E928 and E930. This mode of interaction likely accounts for a more stable and durable α4β1-gC1q interaction in comparison with the prototypic CS1 ligand. To our knowledge, this is the first report describing the simultaneous involvement of all the three acidic residues of a trimeric ligand in the formation of a dimeric complex with the integrin βI domain.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Susanne Homann, Maria Grandoch, Lena S. Kiene, Yanina Podsvyadek, Kathrin Feldmann, Berit Rabausch, Nadine Nagy, Stefan Lehr, Inga Kretschmer, Alexander Oberhuber, Paul Bollyky, Jens W. Fischer

Objective Hyaluronan (HA) is a prominent component of the provisional extracellular matrix (ECM) present in the neointima of atherosclerotic plaques. Here the role of HA synthase 3 (HAS3) in atheroprogression was studied. Approach and results It is demonstrated here that HAS isoenzymes 1, -2 and -3 are expressed in human atherosclerotic plaques of the carotid artery. In Apolipoprotein E (Apoe)-deficient mice Has3 expression is increased early during lesion formation when macrophages enter atherosclerotic plaques. Importantly, HAS3 expression in vascular smooth muscle cells (VSMC) was found to be regulated by interleukin 1 β (IL-1β) in an NFkB dependent manner and blocking antibodies to IL-1β abrogate Has3 expression in VSMC by activated macrophages. Has3/Apoe double deficient mice developed less atherosclerosis characterized by decreased Th1-cell responses, decreased IL-12 release, and decreased macrophage-driven inflammation. Conclusions Inhibition of HAS3-dependent synthesis of HA dampens systemic Th1 cell polarization and reduces plaque inflammation. These data suggest that HAS3 might be a promising therapeutic target in atherosclerosis. Moreover, because HAS3 is regulated by IL-1β, our results suggest that therapeutic anti-IL-1β antibodies, recently tested in human clinical trials (CANTOS), may exert their beneficial effects on inflammation in post-myocardial infarction patients in part via effects on HAS3. TOC categorybasic study TOC subcategoryarteriosclerosis





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Tiantian Wu, Jingwen Huang, Shasha Wu, Zhengjie Huang, Xiaoyan Chen, Yingfu Liu, Dan Cui, Gang Song, Qi Luo, Fan Liu, Gaoliang Ouyang

Periostin (Postn) is a crucial extracellular remodeling factor that has been implicated in the pathogenesis of hepatic inflammation, fibrosis, non-alcoholic fatty liver disease and liver cancer. However, the role of Postn in liver regeneration remains unclear. Here, we demonstrate that Postn mRNA and protein levels are significantly upregulated in the mice after 2/3 partial hepatectomy (PHx). Compared with wild-type mice, Postn-deficient mice exhibit lower liver/body weight ratio and less Ki67-positive cells at days 2, 8 and 14 after PHx. Macrophage infiltration and the levels of TNF-α, IL-6 and HGF in the livers of Postn-deficient mice are significantly decreased compared with wild-type mice one day after PHx. In addition, overexpression of Postn leads to higher liver/body weight ratio and more Ki67-positive cells in the livers of mice and promotes hepatocyte proliferation in vitro. Moreover, liver sinusoidal endothelial cells, biliary epithelial cells and hepatocytes can express Postn after PHx, and Postn deficiency impairs angiogenesis during liver regeneration. Our findings indicate that Postn deficiency impairs liver regeneration in mice after PHx and Postn might be a novel promoter for liver regeneration.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Yeojung Kim, Gail A. West, Greeshma Ray, Sean P. Kessler, Aaron C. Petrey, Claudio Fiocchi, Christine McDonald, Michelle S. Longworth, Laura E. Nagy, Carol A. de la Motte

Tight junction proteins are critical in maintaining homeostatic intestinal permeability. Multiple intestinal inflammatory diseases are correlated with reduced expression of tight junction proteins. We have recently reported that oral treatment of mice with Hyaluronan 35kDa (HA35) increases colonic expression of tight junction protein zonula occludens-1 (ZO-1). Here, we investigate whether HA35 treatment enhances ZO-1 expression by direct interaction with intestinal epithelium in vitro and have identified the HA receptor responsible for HA35-mediated ZO-1 induction in colonic epithelium in vitro and in vivo. Our results reveal that HA35 treatment increases ZO-1 expression in mouse intestinal epithelial organoids, while large HA 2000kDa is not internalized into the cells. Our immunofluorescence data indicate that layilin, but neither toll-like receptor-4 (TLR-4) nor CD44, mediate the HA35-induced ZO-1 expression in colonic epithelium in vitro and in vivo. Additionally, using layilin null mice we have determined that layilin mediates HA35 induction of ZO-1 in healthy mice and during dextran sulfate sodium (DSS)-induced colitis. Furthermore, we find that while ZO-1 expression levels are reduced, layilin expression levels are equivalent in inflammatory bowel disease (IBD) patients and non-IBD controls. Together, our data suggest that layilin is an important HA receptor, that mediates the effect of oral HA35 treatment on intestinal epithelium. HA35 holds promise as a simple dietary supplement to strengthen gut barrier defense.





Publication date: March 2018
Source:Matrix Biology, Volume 66

Author(s): Sophie Deckx, Ward Heggermont, Paolo Carai, Marieke Rienks, Tom Dresselaers, Uwe Himmelreich, Rick van Leeuwen, Wies Lommen, Jolanda van der Velden, Arantxa Gonzalez, Javier Diez, Anna-Pia Papageorgiou, Stephane Heymans

The small leucine-rich proteoglycan osteoglycin has been implicated in matrix homeostasis in different organs, including the ischemic heart. However, whether osteoglycin modulates cardiac hypertrophy, fibrosis or inflammation in hypertensive heart disease and during aging remains unknown. Angiotensin-II-induced pressure overload increases cardiac osteoglycin expression, concomitant with the onset of inflammation and extracellular matrix deposition. Interestingly aging led to decreased cardiac levels of osteoglycin, yet absence of osteoglycin did not affect organ structure or cardiac function up to the age of 18months. However, Angiotensin-II infusion in combination with aging resulted in exaggerated cardiac fibrosis and inflammation in the osteoglycin null mice as compared to wild-type mice, resulting in increased diastolic dysfunction as determined by magnetic resonance imaging. In vitro, stimulation of bone marrow derived macrophages from osteoglycin null mice with Angiotensin-II resulted in significantly higher levels of ICAM-1 as well as pro-inflammatory cytokines and chemokines IL-1β and MCP-1 as compared to WT cells. Further, stimulation of human cardiac fibroblasts with osteoglycin reduced cell proliferation and inhibited TGF-β induced collagen gene expression. In mouse cardiac tissue, osteoglycin expression inversely correlated with TGF-β expression and in cardiac biopsies of aortic stenosis patients, osteoglycin expression is significantly higher than in control biopsies. Interestingly, osteoglycin levels were higher in patients with less severe myocardial fibrosis and overall in the aortic stenosis patients osteoglycin levels negatively correlated with collagen content in the myocardium. In conclusion, osteoglycin expression is increased in the heart in response to pressure overload and its absence results in increased cardiac inflammation and fibrosis resulting in increased diastolic dysfunction.





Publication date: Available online 1 March 2018
Source:Matrix Biology

Author(s): Elizabeth S. Silagi, Irving M. Shapiro, Makarand V. Risbud

Few human tissues have functions as closely linked to the composition of their extracellular matrices as the intervertebral disc. In fact, the hallmark of intervertebral disc degeneration, commonly accompanying low back and neck pain, is the progressive loss of extracellular matrix molecules - specifically the GAG-substituted proteoglycans. While this loss is often associated with increased extracellular catabolism via metalloproteinases and pro-inflammatory cytokines, there is strong evidence that disc degeneration is related to dysregulation of the enzymes involved in GAG biosynthesis. In this review, we discuss those environmental factors, unique to the disc, that control expression and function of XT-1, GlcAT-I, and ChSy/ChPF in the healthy and degenerative state. Additionally, we address the pathophysiology of aberrant GAG biosynthesis and highlight therapeutic strategies designed to augment the loss of extracellular matrix molecules that afflict the degenerative state.





Publication date: Available online 28 February 2018
Source:Matrix Biology

Author(s): Maria Laura Duque Lasio, Beth A. Kozel

Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency.





Publication date: Available online 27 February 2018
Source:Matrix Biology

Author(s): Martin Götte, Ilona Kovalszky







Publication date: Available online 27 February 2018
Source:Matrix Biology

Author(s): Thomas N. Wight

The content of proteoglycans (PGs) is low in the extracellular matrix (ECM) of vascular tissue, but increases dramatically in all phases of vascular disease. Early studies demonstrated that glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and heparan sulfate (HS) accumulate in vascular lesions in both humans and in animal models in areas of the vasculature that are susceptible to disease initiation (such as at branch points) and are frequently coincident with lipid deposits. Later studies showed the GAGs were covalently attached to specific types of core proteins that accumulate in vascular lesions. These molecules include versican (CSPG), biglycan and decorin (DS/CSPGs), lumican and fibromodulin (KSPGs) and perlecan (HSPG), although other types of PGs are present, but in lesser quantities. While the overall molecular design of these macromolecules is similar, there is tremendous structural diversity among the different PG families creating multiple forms that have selective roles in critical events that form the basis of vascular disease. PGs interact with a variety of different molecules involved in disease pathogenesis. For example, PGs bind and trap serum components that accumulate in vascular lesions such as lipoproteins, amyloid, calcium, and clotting factors. PGs interact with other ECM components and regulate, in part, ECM assembly and turnover. PGs interact with cells within the lesion and alter the phenotypes of both resident cells and cells that invade the lesion from the circulation. A number of therapeutic strategies have been developed to target specific PGs involved in key pathways that promote vascular disease. This review will provide a historical perspective of this field of research and then highlight some of the evidence that defines the involvement of PGs and their roles in the pathogenesis of vascular disease.





Publication date: Available online 27 February 2018
Source:Matrix Biology

Author(s): Mariëlle Walraven, Boris Hinz

Organ fibrosis is characterized by the accumulation of disorganized and stiff extracellular matrix (ECM) and represents the final stage of several life-threatening diseases. The progressive replacement of normal tissue by fibrotic ECM impedes organ functionality to the point of failure. Fibrosis affects millions of people worldwide with no effective cure for various reasons: (a) Due to the lack of clinical biomarkers and non-invasive detection methods fibrosis is often diagnosed too late, when organs are already destroyed beyond repair. (b) Fibrosis can be understood as dysregulated tissue repair that evolved robust programs to be able to respond to various injury scenarios. The redundant nature of these programs often evades linear therapeutic strategies. (c) Fibrosis perpetuates itself by establishing conditions that activate normal into fibrogenic cells which, in turn, create a pro-fibrotic environment. ECM takes center stage in the process of fibrosis as a defining feature and thus potential diagnostic biomarker. The ECM is also a main promoter of the disease process by providing lasting physicochemical pro-fibrotic cues to residing and recruiting cells. Effective anti-fibrotic therapies will need to take the lasting (mis-) instructive character of scar ECM into account. To restore organ functionality, it will be important to (re)turn fibrotic scar into functional ECM, for instance by dissolving fibrotic ECM and delivering cells with regenerative potential.





Publication date: Available online 23 February 2018
Source:Matrix Biology

Author(s): Justin R. Fallon, Elizabeth M. McNally

The extracellular matrix (ECM) plays key roles in normal and diseased skeletal and cardiac muscle. In healthy muscle the ECM is essential for transmitting contractile force, maintaining myofiber integrity and orchestrating cellular signaling. Duchenne Muscular Dystrophy (DMD) is caused by loss of dystrophin, a cytosolic protein that anchors a transmembrane complex and serves as a vital link between the actin cytoskeleton and the basal lamina. Loss of dystrophin leads to membrane fragility and impaired signaling, resulting in myofiber death and cycles of inflammation and regeneration. Fibrosis is also a cardinal feature of DMD. In this review, we will focus on two cases where understanding the normal function and regulation of ECM in muscle has led to the discovery of candidate therapeutics for DMD. Biglycan is a small leucine rich repeat ECM protein present as two glycoforms in muscle that have dramatically different functions. One widely expressed form is biglycan proteoglycan (PG) that bears two chondroitin sulfate GAG chains (typically chondroitin sulfate) and two N-linked carbohydrates. The second glycoform, referred to as ‘NG’ (non-glycanated) biglycan, lacks the GAG side chains. NG, but not PG biglycan recruits utrophin, an autosomal paralog of dystrophin, and an NOS-containing signaling complex to the muscle cell membrane. Recombinant NG biglycan can be systemically delivered to dystrophic mice where it upregulates utrophin at the membrane and improves muscle health and function. An optimized version of NG biglycan, ‘TVN-102’, is under development as a candidate therapeutic for DMD. A second matrix-embedded protein being evaluated for therapeutic potential is latent TGFβ binding protein 4 (LTBP4). Identified in a genomic screen for modifiers of muscular dystrophy, LTBP4 binds both TGFβ and myostatin. Genetic studies identified the hinge region of LTBP4 as linked to TGFβ release and contributing to the “hyper-TGFβ” signaling state that promotes fibrosis in muscular dystrophy. This hinge region can be stabilized by antibodies directed towards this domain. Stabilizing the hinge region of LTBP4 is expected to reduce latent TGFβ release and thus reduce fibrosis.





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