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Title: Hyaluronan turnover in hyaluronidase 3- and β-hexosaminidase-deficient mice
Authors: Arja, Vasantha
Supervisor: Triggs-Raine, Barbara (Biochemistry and Medical Genetics)
Examining Committee: Merz, David (Biochemistry and Medical Genetics) Wrogemann, Klaus (Biochemistry and Medical Genetics) Anderson, Judith (Biological Sciences) Srinivasan, Ganesh (Pediatrics adn Child Health) de la Motte, Carol (Pathobiology, Cleveland Clinic, USA)
Graduation Date: May 2010
Keywords: hyaluronan
Issue Date: 8-Apr-2010
Citation: Atmuri, Vasantha (2008). Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation, Matrix Biology 27:653-60
Abstract: Hyaluronan (HA) is a glycosaminoglycan that is abundant in the extracellular matrix of vertebrate cells. Under physiological conditions HA exists in a high-molecular-weight form, whereas HA fragments accumulate at sites of tissue injury and inflammation. Hyaluronidases are a group of enzymes that initiate the breakdown of HA. In humans, six hyaluronidase-like sequences have been identified in two locations, 3p21.3 (HYAL1, HYAL2 and HYAL3) and 7q31.3 (HYAL4, SPAM1 and HYALP1). Deficiency of one of these enzymes, HYAL1, was identified in a patient with Mucopolysaccharidosis IX, a disorder characterized by peri-articular soft masses containing HA-filled lysosomes. Given the broad distribution of HA and the mild phenotype of the patient, it is likely that other hyaluronidases or possibly the exoglycosidases, β-hexosaminidase and β-glucuronidase, are playing a major role in HA degradation. To address the potential role of HYAL3 in HA degradation in health and disease, a Hyal3-deficient mouse model was generated. Hyal3-deficient mice were viable, fertile and appeared to have no gross phenotype. The only difference observed was a subtle change in the cellularity and tissue structure of lungs from aged Hyal3-deficient mice. Further studies focused on analysis of HA homeostasis revealed a significant increase in HA in the airways of Hyal3-deficient lungs. Altered HA homeostasis is observed in rodent models of several lung conditions. In order to further study the role of Hyal3 in lungs, an ovalbumin-challenged inflammation model was generated in Hyal3-deficient mice. A significant increase in lung HA levels and altered distribution of HA in the airways of lungs was detected in ovalbumin-challenged Hyal3-deficient mice. Moreover, lung inflammation and airway resistance were increased in Hyal3-deficient mice after ovalbumin-challenge compared to similarly treated Hyal3-control mice. This suggests HA homeostasis that is altered during Hyal3-deficiency might be directly or indirectly promoting inflammation and airway resistance. Because the reported level of HA accumulation was very low in Hyal1-deficient and Hyal2-deficient mice, and in our studies of Hyal3-deficient mice, we performed preliminary studies to assess a role for an exoglycosidase, β-hexosaminidase, in HA turnover. Our preliminary studies indicate there is no or little HA accumulation in β-hexosaminidase-deficient mouse tissues. To conclude, our study of Hyal3- and β-hexosaminidase-deficient mice suggests that these are not the major enzymes involved in HA degradation
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