fibrin and Ehlers-Danlos-Syndrome

Reduced activity of beta4-galactosyltransferase 7 (beta4GalT-7), an enzyme involved in synthesizing the glycosaminoglycan linkage region of proteoglycans, is associated with the progeroid form of Ehlers-Danlos syndrome (EDS). In the invertebrates Drosophila melanogaster and Caenorhabditis elegans, mutations in beta4GalT-7 affect biosynthesis of heparan sulfate (HS), a modulator of several biological processes relevant to wound repair. We have analyzed structural alterations of HS and their functional consequences in human beta4GalT-7 Arg270Cys mutant EDS and control fibroblasts. HS disaccharide analysis by reversed phase ion-pairing chromatography revealed a reduced sulfation degree of HS paralleled by altered immunostaining patterns for the phage-display anti-HS antibodies HS4E4 and RB4EA12 in beta4GalT-7 mutant fibroblasts. Real-time PCR-analysis of 44 genes involved in glycosaminoglycan biosynthesis indicated that the structural alterations in HS were not caused by differential regulation at the transcriptional level. Scratch wound closure was delayed in beta4GalT-7-deficient cells, which could be mimicked by enzymatic removal of HS in control cells. siRNA-mediated knockdown of beta4GalT-7 expression induced morphological changes in control fibroblasts which suggested altered cell-matrix interactions. Adhesion of beta4GalT-7 deficient cells to fibronectin was increased while actin stress fiber formation was impaired relative to control cells. Also collagen gel contraction was delayed in the beta4GalT-7 mutants which showed a reduced formation of pseudopodia and filopodia, less efficient penetration of the collagen gels and a diminished formation of collagen suprastructures. Our study suggests an HS-dependent basic mechanism behind the altered wound repair phenotype of beta4GalT-7-deficient EDS patients.

Topics: Actins; Animals; Cell Adhesion; Cell Movement; Ehlers-Danlos Syndrome; Female; Fibrin; Fibroblasts; Fibronectins; Galactosyltransferases; Gene Expression Profiling; Glycosaminoglycans; Heparitin Sulfate; Humans; Infant; Male; Mice; Pseudopodia; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stress Fibers; Syndecan-4; Wound Healing

Generalized membranous gingival enlargement due to an accumulation of fibrin deposits associated with severe alveolar bone loss (ligneous periodontitis) is a rare condition, and plasminogen deficiency seems to play a central role in its pathogenesis. However, this condition has not been described in association with syndromes. This article reports a case of ligneous periodontitis in a boy with the classic type of Ehlers-Danlos syndrome (EDS).. A 12-year-old white male presented with generalized gingival overgrowth and severe alveolar bone loss. A physical examination revealed clinical signs of EDS (velvety skin with mild hyperextensibility, marked hypermobility of the limb joints, atrophic scars on his knees, and easy bruising), which is associated with a positive family history for joint hypermobility. A biopsy of gingival tissues was submitted for routine histology, hematoxylin and eosin (H&E), and direct immunofluorescence (antifibrinogen). An evaluation of plasminogen activity was also performed.. Histopathology revealed chronic periodontitis with fibrinoid material deposition, and direct immunofluorescence proved to be positive for fibrin. Functional plasminogen was reduced. A conclusive diagnosis of ligneous periodontitis due to plasminogen deficiency associated with the classic type of EDS was rendered.. Ehlers-Danlos syndrome can be associated with ligneous periodontitis. In the present case, the histologic examination represented an important tool in the differential diagnosis, because it ruled out EDS type VIII as the associated systemic factor to periodontal breakdown.

Topics: Alveolar Bone Loss; Biopsy; Child; Coloring Agents; Ehlers-Danlos Syndrome; Fibrin; Fluorescent Antibody Technique, Direct; Gingival Overgrowth; Humans; Male; Periodontitis; Plasminogen

A 7-year-old girl is described with Ehlers-Danlos syndrome Type VIII. Symptoms mainly consisted of rapid breakdown of the periodontal tissues. The gingiva exhibited the presence of peculiar previously unidentified cell-poor masses resembling fibrin by their staining properties. Possibly, this histologic feature may be a diagnostic aid in Ehlers-Danlos syndrome Type VIII.

Topics: Child; Ehlers-Danlos Syndrome; Female; Fibrin; Gingival Hyperplasia; Humans; Staining and Labeling; Tooth

Topics: Aging; Blood Platelets; Bucladesine; Cells, Cultured; Cytochalasin B; Ehlers-Danlos Syndrome; Epinephrine; Female; Fetus; Fibrin; Fibrinogen; Fibroblasts; Humans; Iodine Radioisotopes; L Cells; Male; Models, Biological; Prostaglandins; Serotonin; Sex Factors; Skin; Vasopressins