title: Reduced type I collagen utilization: a pathogenic mechanism in COL5A1 haplo-insufficient Ehlers-Danlos syndrome.
abstract: To examine mechanisms by which reduced type V collagen causes weakened connective tissues in the Ehlers-Danlos syndrome (EDS), we examined matrix deposition and collagen fibril morphology in long-term dermal fibroblast cultures. EDS cells with COL5A1 haplo-insufficiency deposited less than one-half of hydroxyproline as collagen compared to control fibroblasts, though total collagen synthesis rates are near-normal because type V collagen represents a small fraction of collagen synthesized. Cells from patients with osteogenesis imperfecta (OI) and haplo-insufficiency for proalpha1(I) chains of type I collagen also incorporated about one-half the collagen as controls, but this amount was proportional to their reduced rates of total collagen synthesis. Collagen fibril diameter was inversely proportional to type V/type I collagen ratios (EDS > control > OI). However, a reduction of type V collagen, in the EDS derived cells, was associated with the assembly of significantly fewer fibrils compared to control and OI cells. These data indicate that in cell culture, the quantity of collagen fibrils deposited in matrix is highly sensitive to reduction in type V collagen, far out of proportion to type V collagen's contribution to collagen mass.
authors.affiliation: Division of Human Genetics, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA. richard.wenstrup@cchmc.org
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.forename: Jane B
authors.initials: JB
authors.lastname: Florer
authors.forename: William G
authors.initials: WG
authors.lastname: Cole
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Willing
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
mesh_terms: D018929:Cell Culture Techniques; D024042:Collagen Type I / Q000378:metabolism*; D024062:Collagen Type V / Q000235:genetics* / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005838:Genotype; D006801:Humans; D010641:Phenotype
chemical_list: D024042:Collagen Type I; D024062:Collagen Type V