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https://hdl.handle.net/2440/46820
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Type: | Journal article |
Title: | A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis |
Author: | Martin, D. Atmuri, V. Hemming, R. Farley, J. Mort, J. Byers, S. Hombach-Klonisch, S. Stern, R. Triggs-Raine, B. |
Citation: | Human Molecular Genetics, 2008; 17(13):1904-1915 |
Publisher: | Oxford Univ Press |
Issue Date: | 2008 |
ISSN: | 0964-6906 1460-2083 |
Statement of Responsibility: | Dianna C. Martin, Vasantha Atmuri, Richard J. Hemming, Judith Farley, John S. Mort, Sharon Byers, Sabine Hombach-Klonisch, Robert Stern and Barbara L. Triggs-Raine |
Abstract: | Hyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lysosomal storage disorder, mucopolysaccharidosis (MPS) IX. We have characterized a mouse model of MPS IX and compared its phenotype with the human disease. The targeted Hyal1 allele in this model had a neomycin resistance cassette in exon 2 that replaced 753 bp of the coding region containing the predicted enzyme active site. As a result, Hyal1-/- animals had no detectable wild-type Hyal1 transcript, protein or serum activity. Hyal1 null animals were viable, fertile and showed no gross abnormalities at 1 year and 8 months of age. Histological studies of the knee joint showed a loss of proteoglycans occurring as early as 3 months that progressed with age. An increased number of chondrocytes displaying intense pericellular and/or cytoplasmic HA staining were detected in the epiphyseal and articular cartilage of null mice, demonstrating an accumulation of HA. Elevations of HA were not detected in the serum or non-skeletal tissues, indicating that osteoarthritis is the key disease feature in a Hyal1 deficiency. Hyal3 expression was elevated in Hyal1 null mice, suggesting that Hyal3 may compensate in HA degradation in non-skeletal tissues. Overall, the murine MPS IX model displays the key features of the human disease. |
Keywords: | Joints Animals Mice, Knockout Humans Mice Osteoarthritis Mucopolysaccharidoses Disease Models, Animal Hyaluronoglucosaminidase Glycosaminoglycans Hyaluronic Acid Gene Targeting Phenotype Female Male |
Provenance: | Human Molecular Genetics Advance Access originally published online on March 15, 2008 |
Rights: | Copyright © The Author 2008. Published by Oxford University Press. All rights reserved. |
DOI: | 10.1093/hmg/ddn088 |
Published version: | http://dx.doi.org/10.1093/hmg/ddn088 |
Appears in Collections: | Aurora harvest 6 Paediatrics publications |
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