A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis

• Published in: Human molecular genetics 2008-07, Vol.17 (13), p.1904-1915
• Main Authors: Martin, Dianna C., Atmuri, Vasantha, Hemming, Richard J., Farley, Judith, Mort, John S., Byers, Sharon, Hombach-Klonisch, Sabine, Stern, Robert, Triggs-Raine, Barbara L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Disease Models, Animal; Errors of metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genetics of eukaryotes. Biological and molecular evolution; Glycosaminoglycans - metabolism; Humans; Hyaluronic Acid - blood; Hyaluronoglucosaminidase - genetics; Hyaluronoglucosaminidase - metabolism; Joints - pathology; Male; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Molecular and cellular biology; Mucopolysaccharidoses - complications; Mucopolysaccharidoses - genetics; Mucopolysaccharidoses - physiopathology; Osteoarthritis - complications; Osteoarthritis - genetics; Osteoarthritis - metabolism; Osteoarthritis - physiopathology; Phenotype
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn088

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.