No 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.Lysyl hydroxylase (LH, 2 EC 1.14.11.4) catalyzes the hydroxylation of lysine residues mainly but not exclusively in -X-LysGly-triplets in collagens and proteins with collagen-like sequences (1). The enzyme resides within the endoplasmic reticulum and has three human and mouse isoenzymes, LHs 1-3 (1-7). The hydroxylysine residues formed have two important functions: they are essential for the stability of the intermolecular cross-links that provide the collagen fibrils with their tensile strength and mechanical stability, and they serve as attachment sites for carbohydrate units, either the monosaccharide galactose or the disaccharide glucosylgalactose (1). Collagen cross-link formation occurs in the extracellular matrix and is initiated by the conversion of specific lysine or hydroxylysine residues in the telopeptides, i.e. the short non-triple helical ends of collagen molecules, into the aldehydes allysine or hydroxyallysine, respectively, catalyzed by lysyl oxidase (8). The telopeptides are connected with the triple helical part of an adjacent molecule by difunctional immature cross-links in the characteristic staggered array of collagen molecules in a fibril. The three main fibril-forming collagens, types I, II, and III, have four cross-linking sites, one in each telopeptide and two in the triple helical region, close to its N-and C-terminal ends (9). If the residue in the telopeptide is hydroxyallysine, the difunctional cross-links can mature into trifunctional non-reducible cross-links comprising lysylpyri...

No abstract