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J. Biol. Chem., Vol. 282, Issue 9, 6588-6596, March 2, 2007

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Tissue-specific Changes in the Hydroxylysine Content and Cross-links of Collagens and Alterations in Fibril Morphology in Lysyl Hydroxylase 1 Knock-out Mice^*

Kati Takaluoma^¶, Marjo Hyry^¶, Juha Lantto^¶, Raija Sormunen^||, Ruud A. Bank^**, Kari I. Kivirikko^¶, Johanna Myllyharju^¶1, and Raija Soininen^¶

From the Collagen Research Unit, Biocenter Oulu, ^¶Department of Medical Biochemistry and Molecular Biology, and ^||Department of Pathology, University of Oulu, FIN-90014, Finland and the ^**Department of Oral Cell Biology, Academic Center for Dentistry, 1066 Amsterdam, The Netherlands

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.

Received for publication, September 13, 2006 , and in revised form, November 20, 2006.

^* This work was supported by Grants 200471 and 202469 from the Health Science Council and 44843 from the Finnish Centre of Excellence Programme 2000–2005 of the Academy of Finland and by the S. Juselius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Collagen Research Unit, Biocenter Oulu and Dept. of Medical Biochemistry and Molecular Biology, P.O. Box 5000, 90014 University of Oulu, Finland. Tel.: 358-8-537-5740; Fax: 358-8-537-5811; E-mail: johanna.myllyharju{at}oulu.fi.

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