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.
Martin
Dianna C
DC
Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, MB, Canada R3E 0W3.
Atmuri
Vasantha
V
Hemming
Richard J
RJ
Farley
Judith
J
Mort
John S
JS
Byers
Sharon
S
Hombach-Klonisch
Sabine
S
Csoka
Antonei B
AB
Stern
Robert
R
Triggs-Raine
Barbara L
BL
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D006821:Hyaluronoglucosaminidase / Q000235:genetics* / Q000378:metabolism*; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009083:Mucopolysaccharidoses / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D010003:Osteoarthritis / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010641:Phenotype
D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; C469220:Hyal1 protein, mouse; D006821:Hyaluronoglucosaminidase