title: Tissue-specific changes in the hydroxylysine content and cross-links of collagens and alterations in fibril morphology in lysyl hydroxylase 1 knock-out mice.
abstract: We have generated mice with targeted inactivation of the Plod1 gene for lysyl hydroxylase 1 (LH1). Its human mutations cause Ehlers-Danlos syndrome VIA (EDS VIA) characterized by muscular hypotonia, joint laxity, and kyphoscoliosis. The Plod1(-/-) mice are flaccid and have gait abnormalities. About 15% of them died because of aortic rupture and smooth muscle cells in non-ruptured Plod1(-/-) aortas showed degenerative changes. Collagen fibrils in the Plod1(-/-) aorta and skin had an abnormal morphology. The LH activity level in the Plod1(-/-) skin and aorta samples was 35-45% of that in the wild type. The hydroxylysine content was decreased in all the Plod1(-/-) tissues, ranging from 22% of that in the wild type in the skin to 75 and 86% in the femur and lung. The hydroxylysylpyridinoline crosslinks likewise showed decreases in all the Plod1(-/-) tissues, ranging from 28 and 33% of that in the wild type in the aorta and cornea to 47 and 59% in femur and tendon, while lysylpyridinolines were increased. The hydroxylysines found in the Plod1(-/-) collagens and their cross-links were evidently synthesized by the other two LH isoenzymes. Few data are available on abnormalities in EDS VIA tissues other than the skin. Plod1(-/-) mice offer an in vivo model for systematic analysis of the tissue-specific consequences of the lack of LH1 activity and may also provide a tool for analyzing the roles of connective tissue in muscle function and the complex interactions occurring in the proper assembly of the extracellular matrix.
authors.affiliation: Collagen Research Unit, University of Oulu, FIN-90014, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Takaluoma
authors.forename: Marjo
authors.initials: M
authors.lastname: Hyry
authors.forename: Juha
authors.initials: J
authors.lastname: Lantto
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
authors.forename: Kari I
authors.initials: KI
authors.lastname: Kivirikko
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.forename: Raija
authors.initials: R
authors.lastname: Soininen
mesh_terms: D000818:Animals; D003094:Collagen / Q000737:chemistry*; D004195:Disease Models, Animal; D004535:Ehlers-Danlos Syndrome / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D005684:Gait; D006901:Hydroxylysine / Q000172:deficiency*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009123:Muscle Hypotonia / Q000209:etiology; D010641:Phenotype; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000172:deficiency / Q000235:genetics*; D012871:Skin Diseases / Q000209:etiology; D014018:Tissue Distribution
chemical_list: D006901:Hydroxylysine; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase