The Experts below are selected from a list of 27894 Experts worldwide ranked by ideXlab platform
Cay M Kielty - One of the best experts on this subject based on the ideXlab platform.
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cell Matrix Biology in vascular tissue engineering
Journal of Anatomy, 2006Co-Authors: Simon Stephan, Stephen Ball, Matthew R Williamson, Daniel V Bax, Amanda Lomas, Adrian C Shuttleworth, Cay M KieltyAbstract:We are developing biocompatible small-calibre vascular substitutes based on polymeric scaffolds that incorporate cell-Matrix signals to enhance vascular cell attachment and function. Our graft scaffold comprises an outer electrostatically spun porous polyurethane layer seeded with smooth muscle cells, and a luminal polycaprolactone layer for endothelial cell attachment. Vascular cell adhesion properties of three vascular elastic fibre molecules, tropoelastin, fibrillin-1 and fibulin-5, have been defined, and adhesion fragments optimized. These fragments are being used to coat the scaffolds to enhance luminal endothelial cell attachment, and to regulate smooth muscle cell attachment and function. Tropoelastin-based cell seeding materials are also being developed. In this way, vascular cell-Matrix Biology is enhancing graft design.
William C Parks - One of the best experts on this subject based on the ideXlab platform.
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metalloproteinases a parade of functions in Matrix Biology and an outlook for the future
Matrix Biology, 2015Co-Authors: Suneel S Apte, William C ParksAbstract:This issue of Matrix Biology is devoted to exploring how metalloproteinases - here inclusive of related families of extracellular proteinases - act on extracellular Matrix (ECM) proteins to influence an astonishing diversity of biological systems and diseases. Since their discovery in the 1960's, Matrix metalloproteinases (MMPs) have oft and widely been considered as the principal mediators of ECM destruction. However, as becomes clear from several articles in this issue, MMPs affect processes that both promote and limit ECM assembly, structure, and quantity. Furthermore, it has become increasingly apparent that ECM proteolysis is neither the exclusive function of MMPs nor their only sphere of influence. Thus, other enzymes may be important participants in ECM proteolysis, and indeed they are. The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 repeat) proteinases, BMP/tolloid proteases, and meprins have all emerged as major mechanisms of ECM proteolysis. An aggregate view of proteolysis as an exquisitely specific and crucial post-translational modification of secreted proteins emerges from these reviews. The cumulative evidence strongly suggests that although some MMPs can and do cleave ECM components, notably fibrillar collagens, the majority of these proteinases are not key physiological participants in morphogenesis nor in control of Matrix metabolism in homeostasis or disease. In contrast, deficiency of ADAMTS proteases leads to a remarkable array of morphogenetic defects and connective tissue disorders consistent with a specialized role in turnover of the embryonic provisional ECM and in ECM assembly. Astacin-related proteases emerge into crucial positions in ECM assembly and turnover, although they also have numerous roles related to morphogen and growth factor regulation. To further turn the traditional view on its head, it is clear that many MMPs are key participants in many, diverse immune and inflammation processes rather than ECM proteolysis. The overlap in the activities within and between these families leads to the view that ECM proteolysis, which is indispensable for life, was over-engineered to an extraordinary extent during vertebrate evolution. That these proteinases, which likely evolved within networks regulating morphogenesis, immunity and regeneration, also participate in diseases is a side effect of human longevity. Attempts to inhibit metalloproteinases in human diseases thus require continuing appraisal of their biological roles and cautious evaluation of potential new therapeutic opportunities.
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structural analysis of the alpha 2 integrin i domain procollagenase 1 Matrix metalloproteinase 1 interaction
Journal of Biological Chemistry, 2001Co-Authors: Thomas Stricker, Joann Dumin, S K Dickeson, L Chung, William C Parks, Samuel A. SantoroAbstract:Abstract Previous studies have established that ligation of keratinocyte α2β1integrin by type I collagen induces expression of Matrix metalloproteinase-1 (MMP-1) and that MMP-1 activity is required for the α2β1 integrin-dependent migration of primary keratinocytes across collagenous matrices. We now present evidence that MMP-1 binds the α2β1integrin via the I domain of the α2 integrin subunit. Using an enzyme-linked immunosorbent assay with purified human MMP-1 and recombinant α2 integrin I domain, we showed that the α2 integrin I domain specifically bound in a divalent cation-dependent manner to both the pro and active forms of MMP-1, but not to MMP-3 or MMP-13. Although both the I domain and MMP-1 bind divalent cations, MMP-1 bound, in a divalent cation-dependent manner, to α2 integrin I domains containing metal ion-dependent adhesion sites motif mutations that prevent divalent cation binding to the I domain, demonstrating that the metal ion dependence is a function of MMP-1. Using a series of MMP-1-MMP-3 and MMP-1-MMP-13 chimeras, we determined that both the linker domain and the hemopexin-like domain of MMP-1 were required for optimal binding to the I domain. The α2 integrin/MMP-1 interaction described here extends an emerging paradigm in Matrix Biology involving anchoring of proteinases to the cell surface to regulate their biological activities.
A J Freemont - One of the best experts on this subject based on the ideXlab platform.
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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
Arthritis Research & Therapy, 2007Co-Authors: Christine Le L Maitre, Judith A Hoyland, A J FreemontAbstract: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.
Zena Werb - One of the best experts on this subject based on the ideXlab platform.
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regulation of Matrix Biology by Matrix metalloproteinases
Current Opinion in Cell Biology, 2004Co-Authors: Joni D Mott, Zena WerbAbstract:Matrix metalloproteinases (MMPs) are endopeptidases that contribute to growth, development and wound healing as well as to pathologies such as arthritis and cancer. Until recently, it has been thought that MMPs participate in these processes simply by degrading extracellular Matrix (ECM) molecules. However, it is now clear that MMP activity is much more directed and causes the release of cryptic information from the ECM. By precisely cleaving large insoluble ECM components and ECM-associated molecules, MMPs liberate bioactive fragments and growth factors and change ECM architecture, all of which influence cellular behavior. Thus, MMPs have become a focal point for understanding Matrix Biology.
D S Mcnally - One of the best experts on this subject based on the ideXlab platform.
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the internal mechanical functioning of intervertebral discs and articular cartilage and its relevance to Matrix Biology
Matrix Biology, 2009Co-Authors: M A Adams, P Dolan, D S McnallyAbstract:Degeneration of intervertebral discs and articular cartilage can cause pain and disability. Risk factors include genetic inheritance and age, but mechanical loading also is important. Its influence has been investigated using miniature pressure transducers to measure the distribution of compressive stress (force per unit area) within loaded tissue. The technique quantifies stress concentrations, and detects regions that behave in a fluid-like manner. Intervertebral discs demonstrate a central fluid-like region which normally extends beyond the anatomical nucleus pulposus so that the whole disc functions like a "water bed". With increasing age, the fluid region shrinks and pressure within it falls. Stress concentrations appear in the surrounding anulus fibrosus, with location depending on posture. Stress concentrations become large in degenerated discs, and are intensified by sustained loading or injury. Articular cartilage never exhibits an internal fluid pressure: stress gradients and concentrations normally occur within it, and are intensified by sustained loading. Excessive Matrix stresses can cause pain and progressive damage. They also inhibit Matrix synthesis and stimulate production of Matrix-degrading enzymes. In this way, injury to chondroid tissues can initiate a 'vicious circle' of abnormal Matrix stresses, abnormal metabolism, weakened Matrix, and further injury, which explains many features of their degeneration.