A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis

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.Dianna C. Martin, Vasantha Atmuri, Richard J. Hemming, Judith Farley, John S. Mort, Sharon Byers, Sabine Hombach-Klonisch, Robert Stern and Barbara L. Triggs-Rain

Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation

Hyaluronidases are endoglycosidases that initiate the breakdown of hyaluronan (HA), an abundant component of the vertebrate extracellular matrix. In humans, six paralogous genes encoding hyaluronidase-like sequences have been identified on human chromosomes 3p21.3 (HYAL2–HYAL1–HYAL3) and 7q31.3 (SPAM1–HYAL4–HYALP1). Mutations in one of these genes, HYAL1, were reported in a patient with mucopolysaccharidosis (MPS) IX. Despite the broad distribution of HA, the HYAL1-deficient patient exhibited a mild phenotype, suggesting other hyaluronidase family members contribute to constitutive HA degradation. Hyal3 knockout (Hyal3−/−) mice were generated to determine if HYAL3 had a role in constitutive HA degradation. Hyal3−/− mice were viable, fertile, and exhibited no gross phenotypic changes. X-ray analysis, histological studies of joints, whole-body weights, organ weights and the serum HA levels of Hyal3−/− mice were normal. No evidence of glycosaminoglycan accumulation, including vacuolization, was identified in the Hyal3−/− tissues analyzed. Remarkably, the only difference identified in Hyal3−/− mice was a subtle change in the alveolar structure and extracellular matrix thickness in lung-tissue sections at 12–14 months-of-age. We conclude that HYAL3 does not play a major role in constitutive HA degradation.Vasantha Atmuri, Dianna C. Martin, Richard Hemming, Alex Gutsol, Sharon Byers, Solmaz Sahebjam, James A. Thliveris, John S. Mort, Euridice Carmona, Judy E. Anderson, Shyamala Dakshinamurti, and Barbara Triggs-Rain