Human Molecular Genetics Advance Access originally published online on March 15, 2008
Human Molecular Genetics 2008 17(13):1904-1915; doi:10.1093/hmg/ddn088
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A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis
1 Department of Biochemistry and Medical Genetics and 2 Department of Human Anatomy and Cell Science, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, MB, Canada R3E 0W3 3 Joint Diseases Laboratory, Shriner’s Hospital for Children, 1529 Cedar Avenue, Montreal, QC, Canada H3G 1A6 4 Matrix Biology Unit, Department of Genetic Medicine, Children, Youth and Women’s Health Service, 72 King William Road, North Adelaide, SA 5006, Australia 5 Department of Paediatrics, The University of Adelaide, Adelaide, SA 5000, Australia 6 Department of Pathology, School of Medicine, University of California, San Francisco, CA 94143-0511, USA
* To whom correspondence should be addressed: Tel: +1 2047893218; Fax: +1 2047893900; Email: traine{at}ms.umanitoba.ca
Received December 21, 2007; Revised February 14, 2008; Accepted March 13, 2008
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.
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