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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 ...


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3D Culture

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


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Matrix Biology
Publication date: Available online 16 February 2018
Source:Matrix Biology

Author(s): Eszter Regős, Hadeer Hesham Abdelfattah, Andrea Reszegi, László Szilák, Klára Werling, Gábor Szabó, András Kiss, Zsuzsa Schaff, Ilona Kovalszky, Kornélia Baghy

Increased expression of syndecan-1 is a characteristic feature of human liver cirrhosis. However, no data are available on the significance of this alteration. To address this question we designed a transgenic mouse strain that driven by albumin promoter, expresses human syndecan-1 in the hepatocytes. Liver cirrhosis was induced by thioacetamide in wild type and hSDC1+/+ mice of the identical strain. The process of fibrogenesis, changes in signal transduction and proteoglycan expression were followed. In an in vitro experiment, the effect of syndecan-1 overexpression on the action of TGFβ1 was determined. Human syndecan-1 and TGFβ1 levels were measured by ELISA in the circulation. Without challenge, no morphological differences were observed between wild type and transgenic mice livers, although significant upregulation of phospho-Akt and FAK was observed in the latter. Fibrogenesis in the transgenic livers, characterized by picrosirius staining, collagen type I, and SMA levels, lagged behind that of control in the first and second months. Changes in signal transduction involved in the process of fibrogenesis, as SMAD, MAPK, Akt and GSK, pointed to the decreased effect of TGFβ1, and this was corroborated by the decreased mRNA expression of TIEG and the growth factor itself. In vitro experiments exposing the LX2 hepatic stellate cell line to conditioned media of wild type and syndecan-1 transfected Hep3B cell lines proved that medium with high syndecan-1 content inhibits TGFβ1-induced upregulation of SMA, TIEG, collagen type I and thrombospondin-1 expression. Detection of liver proteoglycans and heparan sulfate level revealed that their amounts are much higher in control transgenic liver, than that in the wild type. However, it decreases dramatically as a result of shedding after hepatic injury. Shedding is likely promoted by the upregulation of MMP14. As syndecan-1 can bind thrombospondin-1, and as our result demonstrated that the same is true for TGFβ1, shed syndecan-1 can remove the growth factor and its activator together into the systemic circulation.Taking together, our results indicate that the effect of syndecan-1 is accomplished on two levels: a, the shedded syndecan can bind, inhibit and remove TGFβ1; b, interferes with the activation of TGFβ1 by downregulation and binding thrombospondin-1, the activator of the growth factor. However, by the end of the fourth month the protective effect was lost, which is explained by the considerable decrease of syndecan-1 and the almost complete loss of heparan sulfate from the surface of hepatocytes.





Publication date: Available online 16 February 2018
Source:Matrix Biology

Author(s): Yi Zhu, Ilja L. Kruglikov, Yucel Akgul, Philipp E. Scherer

Hyaluronic acid (HA, also known as hyaluronan), is a non-sulfated linear glycosaminoglycan polymer consisting of repeating disaccharide units of d-glucuronic acid and N-acetyl-d-glucosamine abundantly present in the extracellular matrix. The sizes of hyaluronic acid polymers range from 5000 to 20,000,000 Da in vivo, and the functions of HA are largely dictated by its size. Due to its high biocompatibility, HA has been commonly used as soft tissue filler as well as a major component of biomaterial scaffolds in tissue engineering. Several studies have implicated that HA may promote differentiation of adipose tissue derived stem cells in vitro or in vivo when used as a supporting scaffold. However, whether HA actually promotes adipogenesis in vivo and the subsequent metabolic effects of this process are unclear. This review summarizes some recent publications in the field and discusses the possible directions and approaches for future studies, focusing on the role of HA in the adipose tissue.





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

Author(s): Naito Kurio, Cheri Saunders, Till E. Bechtold, Imad Salhab, Hyun-Duck Nah, Sayantani Sinha, Paul C. Billings, Maurizio Pacifici, Eiki Koyama

Condylar articular cartilage in mouse temporomandibular joint develops from progenitor cells near the articulating surface that proliferate, undergo chondrogenesis and mature into hypertrophic chondrocytes. However, it remains unclear how these processes are regulated, particularly postnatally. Here we focused on the apical polymorphic layer rich in progenitors and asked whether the phenotype and fate of the cells require signaling by Indian hedgehog (Ihh) previously studied in developing long bones. In condyles in newborn mice, the apical polymorphic/progenitor cell layer was ~10 cell layer-thick and expressed the articular matrix marker Tenascin-C (Tn-C), and the underlying thick cell layer expressed Tn-C as well as the chondrogenic master regulator Sox9. By 1 month, condylar cartilage had gained its full width, but became thinner along its main longitudinal axis and displayed hypertrophic chondrocytes. By 3 months, articular cartilage consisted of a 2–3 cell layer-thick zone of superficial cells and chondroprogenitors expressing both Tn-C and Sox9 and a bottom zone of chondrocytes displaying vertical matrix septa. EdU cell tracing in juvenile mice revealed that conversion of chondroprogenitors into chondrocytes and hypertrophic chondrocytes required about 48 and 72 h, respectively. Notably, EdU injection in 3 month-old mice labeled both progenitors and maturing chondrocytes by 96 h. Conditional ablation of Ihh in juvenile/early adult mice compromised chondroprogenitor organization and function and led to reduced chondroprogenitor and chondrocyte proliferation. The phenotype of mutant condyles worsened over time as indicated by apoptotic chondrocyte incidence, ectopic chondrocyte hypertrophy, chondrocyte column derangement and subchondral bone deterioration. In micromass cultures of condylar apical cells, hedgehog (Hh) treatment stimulated chondrogenesis and alkaline phosphatase (APase) activity, while treatment with HhAntag inhibited both. Our findings indicate that the chondroprogenitor layer is continuously engaged in condylar growth postnatally and its organization and functioning depend on hedgehog signaling.





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

Author(s): Jan-Niklas Schulz, Markus Plomann, Gerhard Sengle, Donald Gullberg, Thomas Krieg, Beate Eckes

Many different diseases are associated with fibrosis of the skin. The clinical symptoms can vary considerably with a broad range from isolated small areas to the involvement of the entire integument. Fibrosis is triggered by a multitude of different stimuli leading to activation of the immune and vascular system that then initiate fibroblast activation and formation of matrix depositing and remodeling myofibroblasts. Ultimately, myofibroblasts deposit excessive amounts of extracellular matrix with a pathological architecture and alterations in growth factor binding and biomechanical properties, which culminates in skin hardening and loss of mobility. Treatment depends certainly on the specific type and cause of the disease, for the autoimmune driven localized and systemic scleroderma therapeutic options are still limited, but recent research has pointed out diverse molecular targets and mechanisms that can be exploited for the development of novel antifibrotic therapy.





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

Author(s): Tomoyuki Nakamura

Cyclical inflation of the lungs depends on the elasticity of lung parenchymal tissues, a mechanical property that is largely determined by elastic fibers and collagen fibers contained therein. Breakdown of elastic fibers in lungs and lack of the ability to repair damaged elastic fibers causes emphysema, and excessive collagen fibrillogenesis in lung parenchyma is critical for the pathogenesis of lung fibrosis. Recent studies revealed that fibulin-3, 4, and 5, which are matricellular proteins collectively termed “short fibulins” or “elastic fibulins”, play crucial roles in the assembly of elastic fibers. Although these fibulins are closely related paralogs with very similar domain structures and sequences, they have independent molecular functions in elastogenesis, as evidenced by different phenotypes in their gene-knockout mice and in patients with mutations in these genes. More recently, emerging evidence suggests that fibulin-4 is also necessary for fibrillar collagen assembly. In this review, I focus on the roles of short fibulins and their associating molecules in the assembly of elastic fibers and collagen fibers. Human diseases caused by mutations in the genes for these molecules are also reviewed. These matricellular proteins could be novel therapeutic targets for emphysema and lung fibrosis.





Publication date: Available online 10 February 2018
Source:Matrix Biology

Author(s): Monica A. Serban, Aleksander Skardal

Hyaluronan is a ubiquitous constituent of mammalian extracellular matrices and, because of its excellent intrinsic biocompatibility and chemical modification versatility, has been widely employed in a multitude of biomedical applications. In this article, we will survey the approaches used to tailor hyaluronan to specific needs of tissue engineering, regenerative and reconstructive medicine and overall biomedical research. We will also describe recent examples of applications in these broader areas, such as 3D cell culture, bioprinting, organoid biofabrication, and precision medicine that are facilitated by the use of hyaluronan as a biomaterial.





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

Author(s): David Oliveira Dias, Christian Göritz

Following lesions to the central nervous system, scar tissue forms at the lesion site. Injury often severs axons and scar tissue is thought to block axonal regeneration, resulting in permanent functional deficits. While scar-forming astrocytes have been extensively studied, much less attention has been given to the fibrotic, non-glial component of the scar. We here review recent progress in understanding fibrotic scar formation following different lesions to the brain and spinal cord. We specifically highlight recent evidence for pericyte-derived fibrotic scar tissue formation, discussing the origin, recruitment, function and therapeutic relevance of fibrotic scarring.





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

Author(s): Antonietta Salustri, Luisa Campagnolo, Francesca Gioia Klinger, Antonella Camaioni

Successful ovulation and oocyte fertilization are essential prerequisites for the beginning of life in sexually reproducing animals. In mammalian fertilization, the relevance of the protein coat surrounding the oocyte plasma membrane, known as zona pellucida, has been widely recognized, while, until not too long ago, the general belief was that the cumulus oophorus, consisting of follicle cells embedded in a hyaluronan rich extracellular matrix, was not essential. This opinion was based on in vitro fertilization procedures, in which a large number of sperms are normally utilized and the oocyte can be fertilized even if depleted of cumulus cells. Conversely, in vivo, only very few sperm cells reach the fertilization site, arguing against the possibility of a coincidental encounter with the oocyte. In the last two decades, proteins required for HA organization in the cumulus extracellular matrix have been identified and the study of fertility in mice deprived of the corresponding genes have provided compelling evidence that this jelly-like coat is critical for fertilization. This review focuses on the advances in understanding the molecular interactions making the cumulus environment suitable for oocyte and sperm encounter. Most of the studies on the molecular characterization of the cumulus extracellular matrix have been performed in the mouse and we will refer essentially to findings obtained in this animal model.





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

Author(s): Nikolaos A. Afratis, Moises Selman, Annie Pardo, Irit Sagi

Fibrosis is the extensive accumulation and buildup of extracellular matrix components, especially fibrillar collagens, during wound healing in response to tissue injury. During all individual stages of fibrosis ECM proteases, mainly matrix metalloproteinases, have diverse roles. The functional role of MMPs and their endogenous inhibitors are differentiated among their family members, and according to the different stages of fibrosis. MMPs levels are elevated in several inflammatory and non-inflammatory fibrotic tissues contributing to the development, progression or resolution of the disease, whereas in other tissues their expression levels can be diminished or be stable to the baseline. The biological roles of MMPs during fibrosis are not fully resolved, but they seem to differ according the specific member of the family, the affected tissue and the stage of the fibrotic response. Remarkably, some members of the family exhibit profibrotic actions while other function as antifibrotic molecules. Diverse animal models indicate that MMPs are contributing in processes related to immunity, tissue repair and ECM turnover, providing significant impact on mechanisms related to fibrosis. For that purpose, these proteases are considered as pharmacological targets and new biological drugs have been developed in order to treat fibrosis.





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

Author(s): David G. Jackson

LYVE-1, a close relative of the leucocyte receptor, CD44, is the main receptor for hyaluronan (HA) in lymphatic vessel endothelium and a widely used marker for distinguishing between blood and lymphatic vessels. Enigmatic for many years because of its anomalous HA-binding characteristics, the function of LYVE-1 has just recently been identified as that of a lymphatic docking receptor for dendritic cells, selectively engaging with their surface HA glycocalyx to regulate entry to peripheral lymphatics and migration to downstream lymph nodes for immune activation. Furthermore, LYVE-1 mediates the trafficking of macrophages, and is also exploited by HA-encapsulated Group A streptococci for lymphatic invasion and host dissemination. Consistent with a role in lymphatic trafficking, the interaction of LYVE-1 with HA and its degradation products can also activate intracellular signalling pathways for endothelial junctional retraction and lymphatic endothelial proliferation. Here we outline the latest findings on the receptor in the context of its peculiar biochemical properties and speculate on how the interaction of LYVE-1 with different HA sizes and conformations might variably influence cell function as a consequence of avidity and receptor crosslinking. Finally, we evaluate evidence that LYVE-1 can also bind growth factors and associate with kinase-linked growth factor receptors and conclude on how the LYVE-1·HA axis may be exploited as a target to either block inflammation or tissue allograft rejection, or potentiate vaccine and drug delivery.





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

Author(s): Warren Knudson, Shinya Ishizuka, Kenya Terabe, Emily B. Askew, Cheryl B. Knudson

The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan—with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.





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

Author(s): Leslie S. Gewin

Tubulointerstitial fibrosis (TIF) is the hallmark of chronic kidney disease and best predictor of renal survival. Many different cell types contribute to TIF progression including tubular epithelial cells, myofibroblasts, endothelia, and inflammatory cells. Previously, most of the attention has centered on myofibroblasts given their central importance in extracellular matrix production. However, emerging data focuses on how the response of the proximal tubule, a specialized epithelial segment vulnerable to injury, plays a central role in TIF progression. Several proximal tubular responses such as de-differentiation, cell cycle changes, autophagy, and metabolic changes may be adaptive initially, but can lead to maladaptive responses that promote TIF both through autocrine and paracrine effects. This review discusses the current paradigm of TIF progression and the increasingly important role of the proximal tubule in promoting TIF both in tubulointerstitial and glomerular injuries. A better understanding and appreciation of the role of the proximal tubule in TIF has important implications for therapeutic strategies to halt chronic kidney disease progression.





Publication date: Available online 2 February 2018
Source:Matrix Biology

Author(s): Robert M. Tighe, Stavros Garantziotis

Lung disease is a leading cause of morbidity and mortality worldwide. Innate immune responses in the lung play a central role in the pathogenesis of lung disease and the maintenance of lung health, and thus it is crucial to understand factors that regulate them. Hyaluronan is ubiquitous in the lung, and its expression is increased following lung injury and in disease states. Furthermore, hyaladherins like inter-α-inhibitor, tumor necrosis factor-stimulated gene 6, pentraxin 3 and versican are also induced and help form a dynamic hyaluronan matrix in injured lung. This review synthesizes present knowledge about the interactions of hyaluronan and its associated hyaladherins with the lung immune system, and the implications of these interactions for lung biology and disease.





Publication date: Available online 2 February 2018
Source:Matrix Biology

Author(s): Lucas R. Smith, Elisabeth R. Barton

The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.





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

Author(s): Xiaohui Zhang, Dong Sun, Jeon W. Song, Joseph Zullo, Mark Lipphardt, Leona Coneh-Gould, Michael S. Goligorsky

Dysfunctional endothelial cells are an essential contributor to the progression of diverse chronic cardiovascular, renal, and metabolic diseases. It manifests in impairment of nitric oxide-dependent vasorelaxation, vascular permeability, and leukocytes deterrent. While endothelial glycocalyx is known to regulate these functions, glycocalyx has been shown to be impaired in pathologic settings leading to endothelial dysfunction. Are these findings coincidental or are they indicative of a potential cooperation of the glycocalyx and the endothelium in inducing a dysfunctional phenotype? The main thrust of this overview is to advance a hypothesis on the existence of vicious circle relations between impaired endothelial glycocalyx and endothelial cell dysfunction. We briefly introduce physiology and pathology of blood flow-induced components of mechanotransduction in endothelial cells, as this function is dependent on glycocalyx and is critically involved in the development of endothelial dysfunction. Next, we present a series of experimental findings and arguments favoring the view on the impairment of mechanotransduction in dysfunctional endothelia. We advance the concept of feedback reinforcement between perturbed endothelial glycocalyx and progression of endothelial dysfunction and sketch therapeutic approaches to restore them. Among those we introduce our recently designed liposomal nanocarriers of preassembled glycocalyx and present evidence of their ability to expeditiously restore endothelial mechanotransduction.





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

Author(s): Matej Vizovišek, Marko Fonović, Boris Turk

Cysteine cathepsins have been for a long time considered to execute mainly nonspecific bulk proteolysis in the endolysosomal system. However, this view has been changing profoundly over the last decade as cathepsins were found in the cytoplasm, nucleus and in the extracellular milieu. Cathepsins are currently gaining increased attention largely because of their extracellular roles associated with disease development and progression. While kept under tight control under physiological conditions, their dysregulated and elevated activity in the extracellular milieu are distinctive hallmarks of numerous diseases such as various cancers, inflammatory disorders, rheumatoid arthritis, bone disorders and heart diseases. In this review, we discuss cysteine cathepsins with a major focus on their extracellular roles and extracellular proteolytic targets beyond degradation of the extracellular matrix. We further highlight the perspectives of cathepsin research and novel avenues in cathepsin-based diagnostic and therapeutic applications.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Paraskevi Heldin, Chun-Yu Lin, Konstantinos Kolliopoulos, Yen-Hsu Chen, Spyros S. Skandalis

The tightly regulated biosynthesis and catabolism of the glycosaminoglycan hyaluronan, as well as its role in organizing tissues and cell signaling, is crucial for the homeostasis of tissues. Overexpression of hyaluronan plays pivotal roles in inflammation and cancer, and markedly high serum and tissue levels of hyaluronan are noted under such pathological conditions. This review focuses on the complexity of the regulation at transcriptional and posttranslational level of hyaluronan synthetic enzymes, and the outcome of their aberrant expression and accumulation of hyaluronan in clinical conditions, such as systemic B-cell cancers, aggressive breast carcinomas, metabolic diseases and virus infection.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Anthony J. Day, Caroline M. Milner

Tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6)1 is an inflammation-associated secreted protein that has been implicated as having important and diverse tissue protective and anti-inflammatory properties, e.g. mediating many of the immunomodulatory and beneficial activities of mesenchymal stem/stromal cells. TSG-6 is constitutively expressed in some tissues, which are either highly metabolically active or subject to challenges from the environment, perhaps providing protection in these contexts. The diversity of its functions are dependent on the binding of TSG-6 to numerous ligands, including matrix molecules such as glycosaminoglycans, as well as immune regulators and growth factors that themselves interact with these linear polysaccharides. It is becoming apparent that TSG-6 can directly affect matrix structure and modulate the way extracellular signalling molecules interact with matrix. In this review, we focus mainly on the literature for TSG-6 over the last 10 years, summarizing its expression, structure, ligand-binding properties, biological functions and highlighting TSG-6's potential as a therapeutic for a broad range of disease indications.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Femke Heindryckx, Jin-Ping Li

Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Weiping Su, Steven Matsumoto, Barbara Sorg, Larry S. Sherman

Adult neurogenesis in mammals is a tightly regulated process where neural stem cells (NSCs), especially in the subgranular zone (SGZ) of the hippocampal dentate gyrus, proliferate and differentiate into new neurons that form new circuits or integrate into old circuits involved in episodic memory, pattern discrimination, and emotional responses. Recent evidence suggests that changes in the hyaluronan (HA)-based extracellular matrix of the SGZ may regulate neurogenesis by controlling NSC proliferation and early steps in neuronal differentiation. These studies raise the intriguing possibility that perturbations in this matrix, including HA accumulation with aging, could impact adult neurogenesis and cognitive functions, and that alterations to this matrix could be beneficial following insults to the central nervous system that impact hippocampal functions.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Andrea H. Györfi, Alexandru E. Matei, Jörg H.W. Distler

Transforming growth factor-β (TGF-β) is widely recognized as a core pathway of fibrosis. Inhibition of TGF-β signaling may thus offer potential for antifibrotic therapies. Long-term inhibition of TGF-β signaling at the level of its isoforms and receptors can be associated with unacceptable adverse effects. However, TGF-β regulates a myriad of intracellular signaling cascades to transmit its profibrotic effects and several of those pathways offer potential for pharmacologic intervention. Moreover, the multiple interactions of TGF-β with other profibrotic pathways also yielded candidates for therapeutic intervention. In this review, we discuss selected targets within the TGF-β pathway with high translational potential.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Alexandra Hauser-Kawaguchi, Leonard G. Luyt, Eva Turley

Hyaluronan is a simple extracellular matrix polysaccharide that actively regulates inflammation in tissue repair and disease processes. The native HA polymer, which is large (>500 kDa), contributes to the maintenance of homeostasis. In remodeling and diseased tissues, polymer size is strikingly polydisperse, ranging from <10 kDa to >500 kDa. In a diseased or stressed tissue context, both smaller HA fragments and high molecular weight HA polymers can acquire pro-inflammatory functions, which result in the activation of multiple receptors, triggering pro-inflammatory signaling to diverse stimuli. Peptide mimics that bind and scavenge HA fragments have been developed, which show efficacy in animal models of inflammation. These studies indicate both that HA fragments are key to driving inflammation and that scavenging these is a viable therapeutic approach to blunting inflammation in disease processes. This mini-review summarizes the peptide-based methods that have been reported to date for blocking HA signaling events as an anti-inflammatory therapeutic approach.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Alexander Nyström, Leena Bruckner-Tuderman

Genetic or acquired destabilization of the dermal extracellular matrix evokes injury- and inflammation-driven progressive soft tissue fibrosis. Dystrophic epidermolysis bullosa (DEB), a heritable human skin fragility disorder, is a paradigmatic disease to investigate these processes. Studies of DEB have generated abundant new information on cellular and molecular mechanisms at play in skin fibrosis which are not only limited to intractable diseases, but also applicable to some of the most common acquired conditions. Here, we discuss recent advances in understanding the biological and mechanical mechanisms driving the dermal fibrosis in DEB. Much of this progress is owed to the implementation of cell and tissue omics studies, which we pay special attention to. Based on the novel findings and increased understanding of the disease mechanisms in DEB, translational aspects and future therapeutic perspectives are emerging.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): F. Drakopanagiotakis, Lukasz Wujak, Malgorzata Wygrecka, P. Markart

Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, fibrotic lung disease leading to respiratory failure and ultimately to death. Being the prototype of interstitial lung diseases, IPF is characterized by marked heterogeneity regarding its clinical course. Despite significant progress in the understanding of its pathogenesis, we still cannot reliably predict the course of the disease and the response to treatment of an individual patient. Non-invasive biomarkers, in particular serum biomarkers, for the (early) diagnosis, differential diagnosis, prognosis and prediction of therapeutic response are urgently needed. Numerous molecules involved in alveolar epithelial cell injury, fibroproliferation and matrix remodeling as well as immune regulation have been proposed as potential biomarkers. Furthermore, genetic variants of TOLLIP, MUC-5B, and other genes are associated with a differential response to treatment and with the development and/or the prognosis of IPF. Additionally, the bacterial signature in IPF lungs, as shown from microbiome analyses, as well as mitochondrial DNA seem to have promising roles as biomarkers. Moreover, combination of multiple biomarkers may identify comprehensive biomarker signatures in IPF patients. However, there is still a long way until these potential biomarkers complete or substitute for the clinical and functional parameters currently available for IPF.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Tobias Kuehl, David Lagares

Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases. In this Review, we discuss recent findings that have demonstrated that activated myofibroblasts, traditionally viewed as apoptosis-resistant cells, are actually “primed for death”. In this state, mitochondria of activated myofibroblasts are loaded with proapoptotic BH3 proteins, which creates a cellular “addiction” to individual antiapoptotic proteins to block prodeath signaling and ensure survival. This creates a novel therapeutic opportunity to treat organ fibrosis by inducing myofibroblast apoptosis with the so-called BH3 mimetic drugs, which have recently shown potent antifibrotic activities in experimental models. Finally, we discuss the potential use of BH3 profiling as a functional tool to diagnose myofibroblast addiction to individual antiapoptotic proteins, which may serve to guide and assign the most effective BH3 mimetic drug for patients with fibrotic disease.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Pardis Pakshir, Boris Hinz

Scarring is part of the normal healing response to tissue injury in all organs and required to rapidly repair acute damages, mostly with extracellular matrix. A variety of different cells are activated into myofibroblasts to produce and remodel the scar matrix. Temporal and spatial coordination of myofibroblast activities with inflammatory macrophages is crucial for the controlled healing process. Miscommunication can result in either insufficient (chronic) or exacerbated (fibrotic) repair. In addition to soluble biochemical signals and intercellular contacts, cell-to-cell communication is mediated by biophysical and chemical signals transmitted through the extracellular matrix. Over the course of healing, the matrix takes over the role of a master coordinator; failure to do so produces poor healing outcomes that reduce organ function. Understanding the mechanical and chemical state of the matrix and its effects on cellular processes will be essential to address diseases that are characterized by dysfunctional matrix, such as fibrosis.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Li Li, Qian Zhao, Wei Kong

Cardiac fibrosis, characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium, distorts the architecture of the myocardium, facilitates the progression of arrhythmia and cardiac dysfunction, and influences the clinical course and outcome in patients with heart failure. This review describes the composition and homeostasis in normal cardiac interstitial matrix and introduces cellular and molecular mechanisms involved in cardiac fibrosis. We also characterize the ECM alteration in the fibrotic response under diverse cardiac pathological conditions and depict the role of matricellular proteins in the pathogenesis of cardiac fibrosis. Moreover, the diagnosis of cardiac fibrosis based on imaging and biomarker detection and the therapeutic strategies are addressed. Understanding the comprehensive molecules and pathways involved in ECM homeostasis and remodeling may provide important novel potential targets for preventing and treating cardiac fibrosis.





Publication date: Available online 31 January 2018
Source:Matrix Biology

Author(s): Katharina Helene Susek, Eva Korpos, Jula Huppert, Chuan Wu, Irina Savelyeva, Frank Rosenbauer, Carsten Müller-Tidow, Steffen Koschmieder, Lydia Sorokin

Hematopoietic stem and progenitor cell (HSPC) functions are regulated by a specialized microenvironment in the bone marrow - the hematopoietic stem cell niche - of which the extracellular matrix (ECM) is an integral component. We describe here the localization of ECM molecules, in particular the laminin α4, α3 and α5 containing isoforms in the bone marrow. Laminin 421 (composed of laminin α4, β2, γ1 chains) is identified as a major component of the bone marrow ECM, occurring abundantly surrounding venous sinuses and in a specialized reticular fiber network of the intersinusoidal spaces of murine bone marrow (BM) in close association with HSPC. Bone marrow from Lama4 −/− mice is significantly less efficient in reconstituting the hematopoietic system of irradiated wildtype (WT) recipients in competitive bone marrow transplantation assays and shows reduced colony formation in vitro. This is partially due to retention of Linc-kit+Sca-1+CD48 long-term and short-term hematopoietic stem cells (LT-HSC/ST-HSC) in the G0 phase of the cell cycle in Lama4 −/− bone marrow and hence a more quiescent phenotype. In addition, the extravasation of WT BM cells into Lama4 −/− bone marrow is impaired, influencing the recirculation of HSPC. Our data suggest that these effects are mediated by a compensatory expression of laminin α5 containing isoforms (laminin 521/522) in Lama4 −/− bone marrow. Collectively, these intrinsic and extrinsic effects lead to reduced HSPC numbers in Lama4 −/− bone marrow and reduced hematopoietic potential.





Publication date: Available online 16 January 2018
Source:Matrix Biology

Author(s): Bakytbek Egemnazarov, Slaven Crnkovic, Bence M. Nagy, Horst Olschewski, Grazyna Kwapiszewska

Fibrosis and remodeling of the right ventricle (RV) are associated with RV dysfunction and mortality of patients with pulmonary hypertension (PH) but it is unknown how much RV fibrosis contributes to RV dysfunction and mortality. RV fibrosis manifests as fibroblast accumulation and collagen deposition which may be excessive. Although extracellular matrix deposition leads to elevated ventricular stiffness, it is not known to which extent it affects RV function. Various animal models of pulmonary hypertension have been established to investigate the role of fibrosis in RV dysfunction and failure. However, they do not perfectly resemble the human disease. In the current review we describe the major characteristics of RV fibrosis, molecular mechanisms regulating the fibrotic process, and discuss how therapeutic targeting of fibrosis might affect RV function.





Publication date: Available online 16 January 2018
Source:Matrix Biology

Author(s): Andrea Huwiler, Josef Pfeilschifter

Over the last decade, various sphingolipid subspecies have gained increasing attention as important signaling molecules that regulate a multitude of physiological and pathophysiological processes including inflammation and tissue remodeling. These mediators include ceramide, sphingosine 1-phosphate (S1P), the cerebroside glucosylceramide, lactosylceramide, and the gangliosides GM3 and Gb3. These lipids have been shown to accumulate in various chronic kidney diseases that typically end in renal fibrosis and ultimately renal failure. This review will summarize the effects and contributions of those enzymes that regulate the generation and interconversion of these lipids, notably the acid sphingomyelinase, the acid sphingomyelinase-like protein SMPDL3B, the sphingosine kinases, the S1P lyase, the glucosylceramide synthase, the GM3 synthase, and the α-galactosidase A, to renal fibrotic diseases. Strategies of manipulating these enzymes for therapeutic purposes and the impact of existing drugs on renal pathologies will be discussed.





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

Author(s): Geir Christensen, Kate M. Herum, Ida G. Lunde

Extracellular matrix remodeling is extensive in several heart diseases and hampers cardiac filling, often leading to heart failure. Proteoglycans have over the last two decades emerged as molecules with important roles in matrix remodeling and fibrosis in the heart. Here we discuss and review current literature on proteoglycans that have been studied in cardiac remodeling. The small leucine rich proteoglycans (SLRPs) are located within the extracellular matrix and are organizers of the matrix structure. Membrane-bound proteoglycans, such as syndecans and glypicans, act as receptors and direct cardiac fibroblast signaling. Recent studies indicate that proteoglycans are promising as diagnostic biomarkers for cardiac fibrosis, and that they may provide new therapeutic strategies for cardiac disease.





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

Author(s): M. Yasuda-Yamahara, M. Rogg, J. Frimmel, P. Trachte, M. Helmstaedter, P. Schroder, M. Schiffer, C. Schell, T.B. Huber

Simplification and retraction of podocyte protrusions, generally termed as foot process effacement, is a uniform pathological pattern observed in the majority of glomerular disease, including focal segmental glomerulosclerosis. However, it is still incompletely understood how the interaction of cortical actin structures, actomyosin contractility and focal adhesions, is being orchestrated to control foot process morphology in health and disease. By uncovering the functional role of fermitin family member 2 (FERMT2 or kindlin-2) in podocytes, we provide now evidence, how cell-extracellular matrix (ECM) interactions modulate membrane tension and actomyosin contractility. A genetic modeling approach was applied by deleting FERMT2 in a set of in vivo systems as well as in CRISPR/Cas9 modified human podocytes. Loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization associated with plasma membrane blebbing and a remodeling of focal adhesions. We further show that FERMT2 knockout podocytes have high levels of RhoA activation and concomitantly increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype. Thus, our findings establish a direct link between cell-matrix adhesions, cortical actin structures and plasma membrane tension allowing to better explain cell morphological changes in foot process effacement.





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

Author(s): Robert P. Mecham

Elastin is expressed in most tissues that require elastic recoil. The protein first appeared coincident with the closed circulatory system, and was critical for the evolutionary success of the vertebrate lineage. Elastin is expressed by multiple cell types in the lung, including mesothelial cells in the pleura, smooth muscle cells in airways and blood vessels, endothelial cells, and interstitial fibroblasts. This highly crosslinked protein associates with fibrillin-containing microfibrils to form the elastic fiber, which is the physiological structure that functions in the extracellular matrix. Elastic fibers can be woven into many different shapes depending on the mechanical needs of the tissue. In large pulmonary vessels, for example, elastin forms continuous sheets, or lamellae, that separate smooth muscle layers. Outside of the vasculature, elastic fibers form an extensive fiber network that originates in the central bronchi and inserts into the distal airspaces and visceral pleura. The fibrous cables form a looping system that encircle the alveolar ducts and terminal air spaces and ensures that applied force is transmitted equally to all parts of the lung. Normal lung function depends on proper secretion and assembly of elastin, and either inhibition of elastin fiber assembly or degradation of existing elastin results in lung dysfunction and disease.





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

Author(s): Sanna Oikari, Tiia Kettunen, Satu Tiainen, Jukka Häyrinen, Amro Masarwah, Mazen Sudah, Anna Sutela, Ritva Vanninen, Markku Tammi, Päivi Auvinen

Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1–3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.





Publication date: Available online 10 January 2018
Source:Matrix Biology

Author(s): Patricia Rousselle, Marine Montmasson, Cécile Garnier

The ability of skin to act as a barrier is primarily determined by cells that maintain the continuity and integrity of skin and restore it after injury. Cutaneous wound healing in adult mammals is a complex multi-step process that involves overlapping stages of blood clot formation, inflammation, re-epithelialization, granulation tissue formation, neovascularization, and remodeling. Under favorable conditions, epidermal regeneration begins within hours after injury and takes several days until the epithelial surface is intact due to reorganization of the basement membrane. Regeneration relies on numerous signaling cues and on multiple cellular processes that take place both within the epidermis and in other participating tissues. A variety of modulators are involved, including growth factors, cytokines, matrix metalloproteinases, cellular receptors, and extracellular matrix components. Here we focus on the involvement of the extracellular matrix proteins that impact epidermal regeneration during wound healing.





Publication date: Available online 10 January 2018
Source:Matrix Biology

Author(s): Mitsuaki Ono, Asuka Masaki, Azusa Maeda, Tina M. Kilts, Emilio S. Hara, Taishi Komori, Hai Pham, Takuo Kuboki, Marian F. Young

Understanding the mechanisms that control cutaneous wound healing is crucial to successfully manage repair of damaged skin. The goal of the current study was to uncover novel extracellular matrix (ECM) components that control the wound healing process. Full thickness skin defects were created in mice and used to show CCN4 up-regulation during wound-healing as early as 1 day after surgery, suggesting a role in inflammation and subsequent dermal migration and proliferation. To determine how CCN4 could regulate wound healing we used Ccn4-KO mice and showed they had delayed wound closure accompanied by reduced expression of Col1a1 and Fn mRNA. Boyden chamber assays using Ccn4-deficient dermal fibroblasts showed they have reduced migration and proliferation compared to WT counterparts. To confirm CCN4 has a role in proliferation and migration of dermal cells, siRNA knockdown and transduction of CCN4 adenoviral transduction were used and resulted in reduced or enhanced migration of human adult dermal fibroblast (hADF) cells respectively. The induced migration of the dermal fibroblasts by CCN4 appears to work via α5β1 integrin receptors that further stimulates down-stream ERK/JNK signaling. The regulation of CCN4 by TNF-α prompted us look further at their potential relationship. Treatment of hADFs with CCN4 and TNF-α alone or together showed CCN4 counteracted the inhibition of TNF-α on COL1A1 and FN mRNA expression and the stimulation of TNF-α on MMP-1 and MMP3 mRNA expression. CCN4 appeared to counterbalance the effects of TNF-α by inhibiting downstream NF-κB/p-65 signaling. Taken together we show CCN4 stimulates dermal fibroblast cell migration, proliferation and inhibits TNF-α stimulation, all of which could regulate wound healing.





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

Author(s): Francoise Coustry, Karen L. Posey, Tristan Maerz, Kevin Baker, Annie M. Abraham, Catherine G. Ambrose, Sabah Nobakhti, Sandra J. Shefelbine, Xiaohong Bi, Michael Newton, Karissa Gawronski, Lindsay Remer, Alka C. Veerisetty, Mohammad G. Hossain, Frankie Chiu, Jacqueline T. Hecht

Mutations in COMP (cartilage oligomeric matrix protein) cause severe long bone shortening in mice and humans. Previously, we showed that massive accumulation of misfolded COMP in the ER of growth plate chondrocytes in our MT-COMP mouse model of pseudoachondroplasia (PSACH) causes premature chondrocyte death and loss of linear growth. Premature chondrocyte death results from activation of oxidative stress and inflammation through the CHOP-ER pathway and is reduced by removing CHOP or by anti-inflammatory or antioxidant therapies. Although the mutant COMP chondrocyte pathologic mechanism is now recognized, the effect of mutant COMP on bone quality and joint health (laxity) is largely unknown. Applying multiple analytic approaches, we describe a novel mechanism by which the deleterious consequences of mutant COMP retention results in upregulation of miR-223 disturbing the adipogenesis - osteogenesis balance. This results in reduction in bone mineral density, bone quality, mechanical strength and subchondral bone thickness. These, in addition to abnormal patterns of ossification at the ends of the femoral bones likely contribute to precocious osteoarthritis (OA) of the hips and knees in the MT-COMP mouse and PSACH. Moreover, joint laxity is compromised by abnormally thin ligaments. Altogether, these novel findings align with the PSACH phenotype of delayed ossification and bone age, extreme joint laxity and joint erosion, and extend our understanding of the underlying processes that affect bone in PSACH. These results introduce a novel finding that miR-223 is involved in the ossification defect in MT-COMP mice making it a therapeutic target.





Publication date: January 2018
Source:Matrix Biology, Volume 65









Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Pauline Nauroy, Sandrine Hughes, Alexandra Naba, Florence Ruggiero

Extracellular matrix (ECM) proteins are major components of most tissues and organs. In addition to their crucial role in tissue cohesion and biomechanics, they chiefly regulate various important biological processes during embryonic development, tissue homeostasis and repair. In essence, ECM proteins were defined as secreted proteins that localized in the extracellular space. The characterization of the human and mouse matrisomes provided the first definition of ECM actors by comprehensively listing ECM proteins and classified them into categories. Because zebrafish is becoming a popular model to study ECM biology, we sought to characterize the zebrafish matrisome using an in-silico gene-orthology-based approach. We report the identification of 1002 genes encoding the in-silico zebrafish matrisome. Using independent validations, we provide evidence for the robustness of the orthology-based approach. Moreover, we evaluated the orthology relationships between human and zebrafish genes at the whole-genome and matrisome levels and showed that the different categories of ECM genes are differentially subjected to evolutionary pressure. Last, we illustrate how the zebrafish matrisome list can be employed to annotate big data using the example of a previously published proteomic study of the skeletal ECM. The establishment of the zebrafish matrisome will undoubtedly facilitate the analysis of ECM components in “-omic” data sets.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Jasper Foolen, Stefania L. Wunderli, Sandra Loerakker, Jess G. Snedeker

Tendinopathy is a widespread and unresolved clinical challenge, in which associated pain and hampered mobility present a major cause for work-related disability. Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue. A fundamental clinical dilemma with this scarring process is whether treatment strategies should focus on healing the affected (disorganized) tissue or strengthen the remaining healthy (anisotropic) tissue. The question was thus asked whether the intrinsic remodeling capacity of tendon-derived cells depends on the organization of the 3D extracellular matrix (isotropic vs anisotropic). Progress in this field is hampered by the lack of suitable in vitro tissue platforms. We aimed at filling this critical gap by creating and exploiting a next generation tissue platform that mimics aspects of the tendon scarring process; cellular response to a gradient in tissue organization from isotropic (scarred/non-aligned) to highly anisotropic (unscarred/aligned) was studied, as was a transient change from isotropic towards highly anisotropic. Strikingly, cells residing in an ‘unscarred’ anisotropic tissue indicated superior remodeling capacity (increased gene expression levels of collagen, matrix metalloproteinases MMPs, tissue inhibitors of MMPs), when compared to their ‘scarred’ isotropic counterparts. A numerical model then supported the hypothesis that cellular remodeling capacity may correlate to cellular alignment strength. This in turn may have improved cellular communication, and could thus relate to the more pronounced connexin43 gap junctions observed in anisotropic tissues. In conclusion, increased tissue anisotropy was observed to enhance the cellular potential for functional remodeling of the matrix. This may explain the poor regenerative capacity of tenocytes in chronic tendinopathy, where the pathological process has resulted in ECM disorganization. Additionally, it lends support to treatment strategies that focus on strengthening the remaining healthy tissue, rather than regenerating scarred tissue.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Preety Panwar, Georgina S. Butler, Andrew Jamroz, Pouya Azizi, Christopher M. Overall, Dieter Brömme

The natural aging process and various pathologies correlate with alterations in the composition and the structural and mechanical integrity of the connective tissue. Collagens represent the most abundant matrix proteins and provide for the overall stiffness and resilience of tissues. The structural changes of collagens and their susceptibility to degradation are associated with skin wrinkling, bone and cartilage deterioration, as well as cardiovascular and respiratory malfunctions. Here, matrix metalloproteinases (MMPs) are major contributors to tissue remodeling and collagen degradation. During aging, collagens are modified by mineralization, accumulation of advanced glycation end-products (AGEs), and the depletion of glycosaminoglycans (GAGs), which affect fiber stability and their susceptibility to MMP-mediated degradation. We found a reduced collagenolysis in mineralized and AGE-modified collagen fibers when compared to native fibrillar collagen. GAGs had no effect on MMP-mediated degradation of collagen. In general, MMP digestion led to a reduction in the mechanical strength of native and modified collagen fibers. Successive fiber degradation with MMPs and the cysteine-dependent collagenase, cathepsin K (CatK), resulted in their complete degradation. In contrast, MMP-generated fragments were not or only poorly cleaved by non-collagenolytic cathepsins such as cathepsin V (CatV). In conclusion, our data indicate that aging and disease-associated collagen modifications reduce tissue remodeling by MMPs and decrease the structural and mechanic integrity of collagen fibers, which both may exacerbate extracellular matrix pathology.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Susan C. MacLauchlan, Nicole E. Calabro, Yan Huang, Meenakshi Krishna, Tara Bancroft, Tanuj Sharma, Jun Yu, William C. Sessa, Frank Giordano, Themis R. Kyriakides

Thrombospondin-2 (TSP2) is a potent inhibitor of angiogenesis whose expression is dynamically regulated following injury. In the present study, it is shown that HIF-1α represses TSP2 transcription. Specifically, in vitro studies demonstrate that the prolyl hydroxylase inhibitor DMOG or hypoxia decrease TSP2 expression in fibroblasts. This effect is shown to be via a transcriptional mechanism as hypoxia does not alter TSP2 mRNA stability and this effect requires the TSP2 promoter. In addition, the documented repressive effect of nitric oxide (NO) on TSP2 is shown to be non-canonical and involves stabilization of hypoxia inducible factor-1a (HIF-1α). The regulation of TSP2 by hypoxia is supported by the in vivo observation that TSP2 has spatiotemporal expression distinct from regions of hypoxia in gastrocnemius muscle following murine hindlimb ischemia (HLI). A role for TSP2 regulation by HIF-1α is supported by the dysregulation of TSP2 expression in SM22α-cre HIF-1α KO mice following HLI. Indeed, there is a reduction in blood flow recovery in the SM22a-cre HIF-1α KO mice compared to littermate controls following HLI surgery, associated with impaired recovery and increased TSP2 levels. Moreover, SM22α-cre HIF-1α KO smooth muscle cells mice have increased TSP2 mRNA levels that persist in hypoxia. These findings identify a novel, ischemia-induced pro-angiogenic mechanism involving the transcriptional repression of TSP2 by HIF-1α.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Vera Bergmeier, Julia Etich, Lena Pitzler, Christian Frie, Manuel Koch, Matthias Fischer, Gunter Rappl, Hinrich Abken, James J. Tomasek, Bent Brachvogel

After skin injury fibroblasts migrate into the wound and transform into contractile, extracellular matrix-producing myofibroblasts to promote skin repair. Persistent activation of myofibroblasts can cause excessive fibrotic reactions, but the underlying mechanisms are not fully understood. We used SMA-GFP transgenic mice to study myofibroblast recruitment and activation in skin wounds. Myofibroblasts were initially recruited to wounds three days post injury, their number reached a maximum after seven days and subsequently declined. Expression profiling showed that 1749 genes were differentially expressed in sorted myofibroblasts from wounds seven days post injury. Most of these genes were linked with the extracellular region and cell periphery including genes encoding for extracellular matrix proteins. A unique panel of core matrisome and matrisome-associated genes was differentially expressed in myofibroblasts and several genes not yet known to be linked to myofibroblast-mediated wound healing were found (e.g. Col24a1, Podnl1, Bvcan, Tinagl1, Thbs3, Adamts16, Adamts19, Cxcl's, Ccl's). In addition, a complex network of G protein-coupled signaling events was regulated in myofibroblasts (e.g. Adcy1, Plbc4, Gnas). Hence, this first characterization of a myofibroblast-specific expression profile at the peak of in situ granulation tissue formation provides important insights into novel target genes that may control excessive ECM deposition during fibrotic reactions.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Ryoko Sato-Nishiuchi, Shaoliang Li, Fumi Ebisu, Kiyotoshi Sekiguchi

Laminins are major components of basement membranes that sustain a wide variety of stem cells. Among 15 laminin isoforms, laminin-511 and its E8 fragment (LM511E8) have been shown to strongly promote the adhesion and proliferation of human pluripotent stem cells. The aim of this study was to endow the cell-adhesive activity of laminin-511 on collagen matrices, thereby fabricating collagen-based culture scaffolds for stem cells with defined composition. To achieve this goal, we utilized the collagen-binding domain (CBD) of fibronectin to immobilize LM511E8 on collagen matrices. CBD was attached to the N-termini of individual laminin chains (α5E8, β1E8, γ1E8), producing LM511E8s having one, two, or three CBDs. While LM511E8 did not bind to collagen, CBD-attached LM511E8s (CBD-LM511E8s) exhibited significant collagen-binding activity, dependent on the number of attached CBDs. Human iPS cells were cultured on collagen-coated plates preloaded with CBD-LM511E8s. Although iPS cells did not attach or grow on collagen, they robustly proliferated on CBD-LM511E8-loaded collagen matrices, similar to the case with LM511E8-coated plates. Importantly, iPS cells proliferated and yielded round-shaped colonies even on collagen gels preloaded with CBD-LM511E8s. These results demonstrate that CBD-attached laminin E8 fragments are promising tools for fabrication of collagen-based matrices having the cell-adhesive activity of laminins.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Ilanit Boyango, Uri Barash, Liat Fux, Inna Naroditsky, Neta Ilan, Israel Vlodavsky

Heparanase is an endoglucuronidase that uniquely cleaves the heparan sulfate side chains of heparan sulfate proteoglycans. This activity ultimately alters the structural integrity of the ECM and basement membrane that becomes more prone to cellular invasion by metastatic cancer cells and cells of the immune system. In addition, enzymatically inactive heparanase was found to facilitate the proliferation and survival of cancer cells by activation of signaling molecules such as Akt, Src, signal transducer and activation of transcription (Stat), and epidermal growth factor receptor. This function is thought to be executed by the C-terminal domain of heparanase (8c), because over expression of this domain in cancer cells accelerated signaling cascades and tumor growth. We have used the regulatory elements of the mouse mammary tumor virus (MMTV) to direct the expression heparanase and the C-domain (8c) to the mammary gland epithelium of transgenic mice. Here, we report that mammary gland branching morphogenesis is increased in MMTV-heparanase and MMTV-8c mice, associating with increased Akt, Stat5 and Src phosphorylation. Furthermore, we found that the growth of tumors generated by mouse breast cancer cells and the resulting lung metastases are enhanced in MMTV-heparanase mice, thus supporting the notion that heparanase contributed by the tumor microenvironment (i.e., normal mammary epithelium) plays a decisive role in tumorigenesis. Remarkably, MMTV-8c mice develop spontaneous tumors in their mammary and salivary glands. Although this occurs at low rates and requires long latency, it demonstrates decisively the pro-tumorigenic capacity of heparanase signaling.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Shyam K. Bandari, Anurag Purushothaman, Vishnu C. Ramani, Garrett J. Brinkley, Darshan S. Chandrashekar, Sooryanarayana Varambally, James A. Mobley, Yi Zhang, Elizabeth E. Brown, Israel Vlodavsky, Ralph D. Sanderson

The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-α, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse. Summary We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.





Publication date: January 2018
Source:Matrix Biology, Volume 65

Author(s): Audrey McAlinden, Kyu-Hwan Shim, Louisa Wirthlin, Soumya Ravindran, Thomas M. Hering







Publication date: Available online 30 December 2017
Source:Matrix Biology

Author(s): Hélène François, Christos Chatziantoniou

Renal fibrogenesis is the common final pathway to all renal injuries that consequently leads to Chronic Kidney Disease (CKD). Renal fibrogenesis corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins, mainly collagens, that ultimately impairs kidney function. Blockade of the renin angiotensin system by Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARBs) was the first strategy that proved efficient to blunt the development of renal fibrogenesis independently of its systemic action on blood pressure. Although this strategy has been published 20years ago, there is to date no novel therapeutic targets that are both safe and efficient in hindering renal fibrogenesis and CKD in humans, nor there is any new biomarker to precisely quantify this process. In our review, we will focus on the most recent pathways leading to fibrogenesis which have a high therapeutic potential in humans and on the most promising biomarkers of renal fibrosis.





Publication date: Available online 28 December 2017
Source:Matrix Biology

Author(s): Elke Roeb

Liver fibrosis, a reversible wound-healing response to chronic cellular injury, reflects a balance between liver repair and progressive substitution of the liver parenchyma by scar tissue. Complex mechanisms that underlie liver fibrogenesis are summarized to provide the basis for generating targeted therapies to reverse fibrogenesis and improve the outcomes of patients with chronic liver disease. This minireview presents some pathophysiological aspects of liver fibrosis as a dynamic process and elucidates matrix metalloproteinases (MMPs) and their role within as well as beyond matrix degradation. Open questions remain, whether inhibition of fibrogenesis or induction of fibrolysis is the key mechanism to resolve fibrosis. And a point of principle might be whether regeneration of liver cirrhosis is possible. Will we ever cure fibrosis?





Publication date: Available online 27 December 2017
Source:Matrix Biology

Author(s): Joanne E. Murphy-Ullrich, Mark J. Suto

Transforming growth factor-β (TGF-β) is a central player in fibrotic disease. Clinical trials with global inhibitors of TGF-β have been disappointing, suggesting that a more targeted approach is warranted. Conversion of the latent precursor to the biologically active form of TGF-β represents a novel approach to selectively modulating TGF-β in disease, as mechanisms employed to activate latent TGF-β are typically cell, tissue, and/or disease specific. In this review, we will discuss the role of the matricellular protein, thrombospondin 1 (TSP-1), in regulation of latent TGF-β activation and the use of an antagonist of TSP-1 mediated TGF-β activation in a number of diverse fibrotic diseases. In particular, we will discuss the TSP-1/TGF-β pathway in fibrotic complications of diabetes, liver fibrosis, and in multiple myeloma. We will also discuss emerging evidence for a role for TSP-1 in arterial remodeling, biomechanical modulation of TGF-β activity, and in immune dysfunction. As TSP-1 expression is upregulated by factors induced in fibrotic disease, targeting the TSP-1/TGF-β pathway potentially represents a more selective approach to controlling TGF-β activity in disease.





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