Human Molecular Genetics Advance Access published online on March 15, 2008
Human Molecular Genetics, 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, 770 Bannatyne Ave., Winnipeg MB R3E 0W3, Canada 2 Joint Diseases Laboratory, Shriner's Hospital for Children, 1529 Cedar Ave., Montreal, QC H3G 1A6, Canada 3 Matrix Biology Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, 72 King William Rd., North Adelaide, SA 5006, Australia. 4 Department of Paediatrics, This University of Adelaide, SA 5000, Australia 5 Department of Human Anatomy and Cell Science, 770 Bannatyne Ave., Winnipeg MB R3E 0W3, Canada 6 Department of Pathology, School of Medicine, University of California, San Francisco, CA 94143-0511, USA
* To whom correspondence should be addressed: Department of Biochemistry and Medical Genetics University of Manitoba, 770 Bannatyne Ave., Winnipeg, MB R3E 0W3 Phone: (204) 789-3218 Fax: (204) 789-3900 e-mail: 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 to the human disease. The targeted Hyal1allele 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. Hyal1null 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 occuring as early as 3 months that progressed with age. An increased number of chondrocytes displaying intense pericellular and/or cytoplasmic HA staining was 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. Hyal3expression was elevatedin 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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