Journal Article

A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis

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

in Human Molecular Genetics

Volume 17, issue 13, pages 1904-1915
Published in print July 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI:
A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis

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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.

Journal Article.  8196 words.  Illustrated.

Subjects: Genetics and Genomics

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