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      Decorin Deficiency Leads to Impaired Angiogenesis in Injured Mouse Cornea


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          Small leucine-rich proteoglycans play important roles in the organization of the extracellular matrix as well as for the regulation of cell behavior; two biological processes that are essential for angiogenesis. We investigated consequences of the targeted ablation of decorin (DCN), biglycan (BGN) and fibromodulin (FMOD) genes on inflammation-induced angiogenesis in the cornea. In wild-type mice, DCN was localized exclusively to the corneal stroma, while FMOD and BGN were more prominently expressed in epithelial cells. Endothelial cells from limbus blood vessels expressed BGN and FMOD, but no DCN. However, after induction of angiogenesis by chemical cauterization, DCN was expressed in the newly formed capillaries, together with BGN and FMOD. Notably, in DCN-deficient mice, the growth of vessels was significantly diminished, whereas it did not significantly change in FMOD- or BGN-deficient animals. Moreover, blood vessels of DCN-deficient mice exhibited a similar expression level of BGN as control mice, while FMOD was increased on day 3 after injury. These results indicate that DCN, in addition to its effects on fibrillogenesis, plays a regulatory role in angiogenesis and that FMOD in endothelial cells may be able to partially substitute for DCN.

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          Most cited references 28

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          Matrix proteoglycans: from molecular design to cellular function.

           Renato Iozzo (1997)
          The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.
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            Lumican Regulates Collagen Fibril Assembly: Skin Fragility and Corneal Opacity in the Absence of Lumican

            Lumican, a prototypic leucine-rich proteoglycan with keratan sulfate side chains, is a major component of the cornea, dermal, and muscle connective tissues. Mice homozygous for a null mutation in lumican display skin laxity and fragility resembling certain types of Ehlers-Danlos syndrome. In addition, the mutant mice develop bilateral corneal opacification. The underlying connective tissue defect in the homozygous mutants is deregulated growth of collagen fibrils with a significant proportion of abnormally thick collagen fibrils in the skin and cornea as indicated by transmission electron microscopy. A highly organized and regularly spaced collagen fibril matrix typical of the normal cornea is also missing in these mutant mice. This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues. Most importantly, these results provide a definitive link between a necessity for lumican in the development of a highly organized collagenous matrix and corneal transparency.
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              Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease.

              The central pathological feature of human kidney disease that leads to kidney failure is the accumulation of extracellular matrix in glomeruli. Overexpression of transforming growth factor-beta (TGF-beta) underlies the accumulation of pathological matrix in experimental glomerulonephritis. Administration of an antibody raised against TGF-beta to glomerulonephritic rats suppresses glomerular matrix production and prevents matrix accumulation in the injured glomeruli. One of the matrix components induced by TGF-beta, the proteoglycan decorin, can bind TGF-beta and neutralize its biological activity, so decorin may be a natural regulator of TGF-beta (refs 3, 4). We tested whether decorin could antagonize the action of TGF-beta in vivo using the experimental glomerulonephritis model. We report here that administration of decorin inhibits the increased production of extracellular matrix and attenuates manifestations of disease, confirming our hypothesis. On the basis of our results, decorin may eventually prove to be clinically useful in diseases associated with overproduction of TGF-beta.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2004
                03 December 2004
                : 41
                : 6
                : 499-508
                aInstitute of Physiological Chemistry and Pathobiochemistry, bInstitute of Experimental Dermatology and Department of Dermatology, cDepartment of Internal Medicine D, and dDepartment of Experimental Ophthalmology, University and University Hospital of Münster, Münster, Germany; eMatrix Biology & Tissue Repair Research Unit, Dental School University of Wales College of Medicine, Cardiff, UK; fDepartment of Dermatology and Allergology, University and University Hospital of Ulm, Ulm, gOrthopedic University Hospital of Regensburg, Regensburg, Germany; hDepartment of Cell and Molecular Biology, University of Lund, Lund, Sweden; iDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pa., and jCraniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Md., USA
                81806 J Vasc Res 2004;41:499–508
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 42, Pages: 10
                Research Paper


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