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      Proteoglycan synthesis by human corneal explants submitted to laser in situ keratomileusis (LASIK)


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          To evaluate the acute effects of laser in situ keratomileusis (LASIK) upon the synthesis of proteoglycans (PGs) and collagen fibril organization in human corneal explants.


          Human corneas that had been rejected for transplants were obtained at Banco de Olhos of Hospital São Paulo. For each eye pair, one cornea was submitted to refractive surgery, and the other was used as its matched control. After surgery, the corneas were excised from the eyes and immediately placed in a Ham F-12 nutrient mixture containing 35S-sulfate for the metabolic labeling of PGs. After 24 h incubation, PGs were extracted and identified by a combination of agarose gel electrophoresis and enzymatic degradation with protease and specific glycosaminoglycan lyases. Histopathological and birefringence analysis were performed in fixed tissue slices.


          A marked decrease in 35S-sulfate incorporation in PGs was observed in corneal explants that received LASIK, especially concerning dermatan sulfate-PGs, with keratan sulfate- and heparan sulfate-PG synthesis reduced to a lower degree. Only low molecular weight PGs were present in the corneas, both before and 24 h after LASIK. No sign of wound healing processes were observed, but a marked change in corneal birefringence was seen following LASIK treatment.


          Laser application led to decreased PG biosynthesis in human corneal explants, with marked changes in the collagen fibril organization, as revealed by changes in the tissue birefringence.

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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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            Collagens and proteoglycans of the corneal extracellular matrix

            The cornea is a curved and transparent structure that provides the initial focusing of a light image into the eye. It consists of a central stroma that constitutes 90% of the corneal depth, covered anteriorly with epithelium and posteriorly with endothelium. Its transparency is the result of the regular spacing of collagen fibers with remarkably uniform diameter and interfibrillar space. Corneal collagen is composed of heterotypic fibrils consisting of type I and type V collagen molecules. The cornea also contains unusually high amounts of type VI collagen, which form microfibrillar structures, FACIT collagens (XII and XIV), and other nonfibrillar collagens (XIII and XVIII). FACIT collagens and other molecules, such as leucine-rich repeat proteoglycans, play important roles in modifying the structure and function of collagen fibrils.Proteoglycans are macromolecules composed of a protein core with covalently linked glycosaminoglycan side chains. Four leucine-rich repeat proteoglycans are present in the extracellular matrix of corneal stroma: decorin, lumican, mimecan and keratocan. The first is a dermatan sulfate proteoglycan, and the other three are keratan sulfate proteoglycans. Experimental evidence indicates that the keratan sulfate proteoglycans are involved in the regulation of collagen fibril diameter, and dermatan sulfate proteoglycan participates in the control of interfibrillar spacing and in the lamellar adhesion properties of corneal collagens. Heparan sulfate proteoglycans are minor components of the cornea, and are synthesized mainly by epithelial cells. The effect of injuries on proteoglycan synthesis is discussed.
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              Mapping collagen organization in the human cornea: left and right eyes are structurally distinct.

              Aspects of the biomechanics and surface topography of fellow human corneas are known to exhibit midline symmetry, but the structural basis of these observations is poorly understood. The mechanical performance of the cornea is strongly influenced by the organization of stromal collagen fibrils. The present study was designed to examine and compare the organization of collagen fibrils in the corneal stroma of left and right eyes. Wide-angle x-ray scattering was used to map in detail the orientation and distribution of fibrillar collagen across the cornea, limbus, and adjacent sclera of three normal human eyes, including a fellow pair, and the central 9-mm corneal region of a further four eyes. Fibrillar collagen in the human cornea and limbus is arranged anisotropically, and in a highly specific manner. Left and right corneas are structurally distinct. In general, the mass distribution of preferentially aligned fibrils in the cornea appears to exhibit a degree of midline symmetry between left and right eyes. Structural information, such as that presented herein, will enable a better understanding of corneal biomechanics and shape. Midline symmetry in the distribution of aligned, mechanically reinforcing collagen fibrils between left and right eyes may relate to the biomechanical and topographical enantiomorphism reported in the literature.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                01 February 2007
                : 13
                : 142-150
                [1 ]Departamento de Oftalmologia, Universidade Federal de São Paulo, Escola Paulista de Medicina - UNIFESP - São Paulo, SP, Brazil
                [2 ]Departamento de Biologia Celular, Universidade de Campinas, Campinas, SP, Brazil
                [3 ]Departamento de Bioquímica, Universidade Federal de São Paulo, Escola Paulista de Medicina - UNIFESP - São Paulo-SP, Brazil
                Author notes
                Correspondence to: Yara M. Michelacci, PhD., Departamento de Bioquímica, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua 3 de maio 100, São Paulo-SP, Brazil, 04044-020; Phone (5511) 5576-4442; FAX: (5511) 5573-6407; email: yara.bioq@epm.br
                17 2006MOLVIS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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