Matrix Biology Research Articles

Is Pathologic Intimal Thickening the Key to Understanding Early Plaque Progression in Human Atherosclerotic Disease?

The term “ P athologic I ntimal T hickening” (PIT) was recently introduced to define an early stage of atherosclerosis described in human coronary lesions found at autopsies of sudden death victims.1 This descriptive identifier is based on the AHA type III (intermediate) lesion and, as originally presented by Stary and collegues, it’s believed to be the morphological and chemical bridge to more advanced plaques.2 The precise histological features and clinical relevance of PIT remains unsettled, and use of the term is still far from widespread. In short, PIT identifies a lesion with an extracellular lipid pool with intimal smooth muscle cell loss typically adjacent to the medial wall in addition to varying degrees of macrophage infiltration near the lumen. These morphological features indicate a progressive lesion in the earlier stages of atherosclerosis, although there is yet the presence of a necrotic core. As recently studied by Nakashima and colleagues in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , it may provide a key in settling the chicken-versus-egg debate of atherosclerotic plaque progression: does lipid come first, or do macrophages?3 Is PIT the precursor lesion of fibroatheroma? The study in this issue uses 3-dimensional histology to attempt to address some of these issues, and, in doing so, may raise as many questions as it answers. See page 1159 Although there are many detailed autopsy studies describing various lesion morphologies, little is known how human atherosclerosis progresses from early to more advanced plaques, marked by the formation of a necrotic core. This important question remains, in part, from a lack of direct experimental testing in prospective models of human disease. Moreover, potentially relevant finding in animals are difficult to associate with humans because the pathologic change of atherosclerosis in man cannot be definitely equated with animals. Although …

Can matrix metalloproteinase inhibitors provide a realistic therapy in cardiovascular medicine?

Tissue matrix biology has provided potential new mechanisms to control vascular and cardiac ageing if effective means of modifying its control processes can be developed. Changing patterns of matrix composition are well documented in a range of cardiovascular disease processes. Locally active metalloproteinases are known to be mediators of composition but their integration and clinical study is severely limited by low specificity and sensitivity of measures in blood that are not clearly relevant to tissue response. The majority of research involving matrix metalloproteinase inhibition is in cancer management; however, the potential of cardiovascular application of these therapies remains relatively untested. Although there remain significant practical problems to be solved, the importance and therapeutic potential of matrix biology in cardiovascular disease is not in question. It is likely that adjuvant use of matrix metalloproteinase inhibitors can significantly enhance the efficacy of current effective cardiovascular treatments for coronary disease, vascular atherosclerosis, ectasia and aneurysm, collateral vessel development and myocardial remodeling.

Transcription Profiling of Adult and Fetal Human Neuroprogenitors Identifies Divergent Paths to Maintain the Neuroprogenitor Cell State

Global gene expression profiling was performed using RNA from adult human hippocampus-derived neuroprogenitor cells (NPCs) and multipotent frontal cortical fetal NPCs compared with adult human mesenchymal stem cells (hMSCs) as a multipotent adult stem cell control, and adult human hippocampal tissue, to define a gene expression pattern that is specific for human NPCs. The results were compared with data from various databases. Hierarchical cluster analysis of all neuroectodermal cell/tissue types revealed a strong relationship of adult hippocampal NPCs with various white matter tissues, whereas fetal NPCs strongly correlate with fetal brain tissue. However, adult and fetal NPCs share the expression of a variety of genes known to be related to signal transduction, cell metabolism and neuroectodermal tissue. In contrast, adult NPCs and hMSCs overlap in the expression of genes mainly involved in extracellular matrix biology. We present for the first time a detailed transcriptome analysis of human adult NPCs suggesting a relationship between hippocampal NPCs and white matter-derived precursor cells. We further provide a framework for standardized comparative gene expression analysis of human brain-derived NPCs with other stem cell populations or differentiated tissues. Disclosure of potential conflicts of interest is found at the end of this article.

P229 Evaluation of the biology of matrix associated autologous chondrocyte transplantation (MACT) in an equine model: results of a pilot study

P229 Evaluation of the biology of matrix associated autologous chondrocyte transplantation (MACT) in an equine model: results of a pilot study

Abstracts submitted to the Vascular Matrix Biology and Bioengineering Workshop Presented March 15–18, 2007 in Whistler, British Columbia Sponsored by the North American Vascular Biology Organization Co-sponsored by the Canadian Society of Atherosclerosis, Thrombosis and Vascular Biology

Journal of Tissue Engineering and Regenerative MedicineVolume 1, Issue 3 p. 218-242 Abstract Abstracts submitted to the Vascular Matrix Biology and Bioengineering Workshop Presented March 15–18, 2007 in Whistler, British Columbia Sponsored by the North American Vascular Biology Organization Co-sponsored by the Canadian Society of Atherosclerosis, Thrombosis and Vascular Biology Organized by: Cecilia M. Giachelli, University of Washington and Michelle P. Bendeck, University of Toronto First published: 08 June 2007 https://doi.org/10.1002/term.29AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume1, Issue3May/June 2007Pages 218-242 RelatedInformation

Microfibril-associated MAGP-2 Stimulates Elastic Fiber Assembly

Elastic fibers are complex structures composed of a tropoelastin inner core and microfibril outer mantle guiding tropoelastin deposition. Microfibrillar proteins mainly include fibrillins and microfibril-associated glycoproteins (MAGPs). MAGP-2 exhibits developmental expression peaking at elastic fiber onset, suggesting that MAGP-2 mediates elastic fiber assembly. To determine whether MAGP-2 regulates elastic fiber assembly, we used an in vitro model featuring doxycycline-regulated cells conditionally overexpressing exogenous MAGP-2 and constitutively expressing enhanced green fluorescent protein-tagged tropoelastin. Analysis by immunofluorescent staining showed that MAGP-2 overexpression dramatically increased elastic fibers levels, independently of extracellular levels of soluble tropoelastin, indicating that MAGP-2 stimulates elastic fiber assembly. This was associated with increased levels of matrix-associated MAGP-2. Electron microscopy showed that MAGP-2 specifically associates with microfibrils and that elastin globules primarily colocalize with MAGP-2-associated microfibrils, suggesting that microfibril-associated MAGP-2 facilitates elastic fiber assembly. MAGP-2 overexpression did not change levels of matrix-associated fibrillin-1, MAGP-1, fibulin-2, fibulin-5, or emilin-1, suggesting that microfibrils and other elastic fiber-associated proteins known to regulate elastogenesis do not mediate MAGP-2-induced elastic fiber assembly. Moreover, mutation analysis showed that MAGP-2 does not stimulate elastic fiber assembly through its RGD motif, suggesting that integrin receptor binding does not mediate MAGP-2-induced elastic fiber assembly. Because MAGP-2 interacts with Jagged-1 that controls cell-matrix interaction and cell motility, two key factors in elastic fiber macroassembly, microfibril-associated MAGP-2 may stimulate elastic fiber macroassembly by targeting the release of elastin globules from the cell membrane onto developing elastic fibers.

Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study

Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs. ISZ employed three substrates (gelatin, collagen, casein) and different challenges (IL-1β, IL-1Ra and enzyme inhibitors). Immunohistochemistry was undertaken for MDPs. In addition, IL-1Ra was introduced into degenerate IVD explants using genetically engineered constructs. The novel findings from this study are: IL-1Ra delivered directly onto explants of degenerate IVDs eliminates matrix degradation as assessed by multi-substrate ISZ; there is a direct relationship between matrix degradation assessed by ISZ and MDP expression defined by immunohistochemistry; single injections of IVD cells engineered to over-express IL-1Ra significantly inhibit MDP expression for two weeks. Our findings show that IL-1 is a key cytokine driving matrix degradation in the degenerate IVD. Furthermore, IL-1Ra delivered directly or by gene therapy inhibits IVD matrix degradation. IL-1Ra could be used therapeutically to inhibit degeneration of the IVD.

MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells

Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

The biology of hernias and the abdominal wall

The fundamental mechanism for hernia formation is loss of the mechanical integrity of abdominal wall structural tissue that results in the inability to offset and contain intra-abdominal forces during valsalva and loading of the torso. There is evidence that genetic or systemic extracellular matrix disorders may predispose patients to hernia formation. There is also evidence that acute laparotomy wound failure leads to hernia formation and increases the risk of recurrent hernia disease. It may be that hernia formation is a heterogeneous disease, not unlike cancer, where one population of patients express an extracellular matrix defect leading to primary hernia disease, while other subsets of patients acquire a defective, chronic wound phenotype following failed laparotomy and hernia repairs. It is evident that an improved understanding of structural tissue matrix biology will lead to improved results following abdominal wall reconstructions.

Gene expression analysis in a canine model of X-linked Alport syndrome

Chronic kidney disease (CKD) often culminates in renal failure as a consequence of progressive interstitial fibrosis and is an important cause of illness and death in dogs. Identification of disease biomarkers and gene expression changes will yield valuable information regarding the specific biological pathways involved in disease progression. Toward these goals, gene expression changes in the renal cortex of dogs with X-linked Alport syndrome (XLAS) were examined using microarray technology. Extensive changes in inflammatory, metabolic, immune, and extracellular matrix biology were revealed in affected dogs. Statistical analysis showed 133 genes that were robustly induced or repressed in affected animals relative to age-matched littermates. Altered expression of numerous major histocompatibility complex (MHC) molecules suggests that the immune system plays a significant role in XLAS. Increased expression of COL4A1 and TIMP-1 at the end stage of disease supports the suggestion that expression increases in association with progression of fibrosis and confirms an observation of increased COL4A1 protein expression. Clusterin may function as one of the primary defenses of the renal cortex against progressive injury in dogs with XLAS, as demonstrated here by increased CLU gene expression. Cellular mechanisms that function during excess oxidative stress might also act to deter renal damage, as evidenced by alterations in gene expression of SOD1, ACO1, FDXR, and GPX1. This investigation provides a better understanding of interstitial fibrosis pathogenesis, and potential biomarkers for early detection, factors that are essential to discovering more effective treatments thereby reducing clinical illness and death due to CKD.

P.P.7 05 Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle

Mutations in the extracellular matrix molecule collagen type VI underlie the congenital muscular dystrophies types Ullrich and Bethlem. The question of the origin of collagen VI in muscle is of interest from a matrix biology point of view and also in view of future treatment approaches that may require cell specific delivery. We therefore examined the production of collagen VI in pure cultures of primary myogenic cells (mononucleated myoblasts and polynucleated myotubes) and muscle interstitial fibroblasts from limb muscle of neonatal BL/6 mouse.

Regenerative medicine and opportunities for engineering clinically relevant tissues

Regenerative medicine is a multidisciplinary field, the goal of which is the repair and replacement of damaged cells, tissues and organs. Recent advances in tissue engineering and regenerative medicine are providing new therapeutic possibilities. In fact, various technological modalities have now enabled the development of biological substitutes for the restoration and maintenance of normal function. Our strategy employs biocompatible matrices in the absence or presence of cells. Thus, matrices are either used as cell delivery vehicles, or alternatively, as scaffolds to promote and enhance tissue formation/regeneration. When cells are used, donor tissue is obtained from the native organ to be replaced and dissociated into individual cells. Cells are expanded in culture, attached to a support matrix, and re-implanted after expansion (autologous), thus avoiding rejection. When native tissues are not available, different stem cell sources may be explored. However, to successfully engineer tissues for clinical use, understanding of cell and matrix biology as well as the internal milieu is required. Since every tissue is unique in its character and function, a careful translational design is necessary. Factors critical to tissue reconstitution include the capacity for in vitro cell growth and expansion, availability of organ-specific biomaterials, favorable cell-biomaterial interactions, appropriate design of three-dimensional constructs, and the use of integrated systems for the enhancement of neo-vascularization and innervation. Opportunities for clinical utility and current challenges hampering organ development will be discussed.

Epidermal Development and Wound Healing in Matrix Metalloproteinase 13-Deficient Mice

Degradation of the extracellular matrix, which is an indispensable step in tissue remodelling processes such as embryonic development and wound healing of the skin, has been attributed to collagenolytic activity of members of the matrix metalloproteinase family (MMPs). Here, we employed mmp13 knockout mice to elucidate the function of MMP13 in embryonic skin development, skin homeostasis, and cutaneous wound healing. Overall epidermal architecture and dermal composition of non-injured skin were indistinguishable from wild-type mice. Despite robust expression of MMP13 in the early phase of wound healing, wild-type and mmp13 knockout animals did not differ in their efficiency of re-epithelialization, inflammatory response, granulation tissue formation, angiogenesis, and restoration of basement membrane. Yet, among other MMPs also expressed during wound healing, MMP8 was found to be enhanced in wounds of MMP13-deficient mice. In summary, skin homeostasis and also tissue remodelling processes like embryonic skin development and cutaneous wound healing are independent of MMP13 either owing to MMP13 dispensability or owing to functional substitution by other collagenolytic proteinases such as MMP8.

British Society for Matrix Biology Autumn 2005, 25th Anniversary Meeting

International Journal of Experimental PathologyVolume 87, Issue 1 p. A1-A58 British Society for Matrix Biology Autumn 2005, 25th Anniversary Meeting First published: 23 January 2006 https://doi.org/10.1111/j.0959-9673.2006.00458.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume87, Issue1February 2006Pages A1-A58 RelatedInformation

A new era of opportunities in lung research

The American Journal of Physiology–Lung Cellular and Molecular Physiology was introduced in 1989. During the past 17 years, the Journal has grown to have a major impact on pulmonary and respiratory sciences. The Journal has published volumes of original and important research on lung and

Plasticity of Mesangial Cells: A Basis for Understanding Pathological Alterations

In the last two decades, the ability of mesangial cells to respond to various stimuli or injurious agents by altering their phenotype and function has become recognized. The plasticity of these mesangial cells has been linked to the morphological and functional alterations responsible for the pathologic findings. Many of the glomerular disorders target the mesangium as the primary and/or initial site of injury. Understanding how mesangial cells are altered in the various conditions provides a platform for conceptualizing pathologic mechanisms and defining key steps amenable to therapeutic intervention. The present paper reviews the normal and altered mesangium with an emphasis on mechanisms involved in alterations of mesangial homeostasis. Mesangial cells and matrix are very important in maintaining normal glomerular structure, and function and the plasticity of these cells is responsible for pathological manifestations, repair, and scarring. Our more sophisticated understanding of mesangial cell behavior and matrix biology provides very useful information to help design new therapeutic approaches to the treatment of renal diseases. The potential for bone marrow-derived cells to differentiate into mesangial cells and repopulate damaged mesangium, thus “healing” what is today considered to be irreversible damage represents an exciting new area of research.

The enamel organic matrix: structure and function

Dental enamel is the most mineralized tissue in the vertebrate body and contains the largest known biologically formed hydroxyapatite crystals. Its formation occurs extracellularly through the collaboration of a proteic transient framework (the enamel organic matrix), which controls hydroxyapatite crystal growth, morphology and orientation. This matrix is deposited with a small amount of mineral during the secretory stage of amelogenesis. The organic components begin to be degraded in the transition stage and are extensively corrupted, and almost entirely replaced by the inorganic crystallites during maturation stage. The present paper reviews current knowledge on the structural biology of the enamel organic matrix.

Relationships between tissue dilatation and differentiation in distraction osteogenesis

Mechanical factors modulate the morphogenesis and regeneration of mesenchymally derived tissues via processes mediated by the extracellular matrix (ECM). In distraction osteogenesis, large volumes of new bone are created through discrete applications of tensile displacement across an osteotomy gap. Although many studies have characterized the matrix, cellular and molecular biology of distraction osteogenesis, little is known about relationships between these biological phenomena and the local physical cues generated by distraction. Accordingly, the goal of this study was to characterize the local physical environment created within the osteotomy gap during long bone distraction osteogenesis. Using a computational approach, we quantified spatial and temporal profiles of three previously identified mechanical stimuli for tissue differentiation-pressure, tensile strain and fluid flow-as well as another candidate stimulus-tissue dilatation (volumetric strain). Whereas pressure and fluid velocity throughout the regenerate decayed to less than 31% of initial values within 20 min following distraction, tissue dilatation increased with time, reaching steady state values as high as 43% strain. This dilatation created large reductions and large gradients in cell and ECM densities. When combined with previous findings regarding the effects of strain and of cell and ECM densities on cell migration, proliferation and differentiation, these results indicate two mechanisms by which tissue dilatation may be a key stimulus for bone regeneration: (1) stretching of cells and (2) altering cell and ECM densities. These results are used to suggest experiments that can provide a more mechanistic understanding of the role of tissue dilatation in bone regeneration.

Tropoelastin Interacts with Cell-surface Glycosaminoglycans via Its COOH-terminal Domain

Using a biochemical and cell biological approach, we have identified a cell interaction site at the carboxyl terminus of tropoelastin. Cell interactions with the COOH-terminal sequence are not through the elastin-binding protein (EBP67) because neither VGVAPG-like peptides nor galactoside sugars altered adhesion. Our results also show that cell adhesion to tropoelastin is not promoted by integrins. Through the use of mutant Chinese hamster ovary cell lines defective in glycosaminoglycan biosynthesis, as well as competition studies and enzymatic removal of specific cell-surface glycosaminoglycans, the tropoelastin-binding moieties on the cell surface were identified as heparan and chondroitin sulfate-containing glycosaminoglycans, with heparan sulfate being greatly preferred. Heparin affinity chromatography combined with cell adhesion assays identified the last 17 amino acids as the sequence element at the carboxyl terminus of tropoelastin responsible for the adhesive activity.

British Society for Matrix Biology Spring 2005 Meeting University of Liverpool

International Journal of Experimental PathologyVolume 86, Issue 6 p. A57-A94 British Society for Matrix Biology Spring 2005 Meeting University of Liverpool First published: 24 November 2005 https://doi.org/10.1111/j.0959-9673.2005.00454.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume86, Issue6December 2005Pages A57-A94 RelatedInformation