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Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?

Laurence Jadin^*, Xiaoli Wu, Hao Ding, Gregory I. Frost, Cécile Onclinx^*, Barbara Triggs-Raine and Bruno Flamion^*,1

^* URPhyM, Laboratory of Physiology and Pharmacology, University of Namur, Namur, Belgium;

Department of Biochemistry and Medical Genetics, The University of Manitoba, Winnipeg, Manitoba, Canada; and

Halozyme Therapeutics, San Diego, California, USA

¹Correspondence: URPhyM, Laboratory of Physiology and Pharmacology, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. E-mail: bruno.flamion{at}fundp.ac.be

The metabolism of hyaluronan (HA) relies on HA synthases and hyaluronidases, among which hyaluronidase-1 (HYAL1) and -2 (HYAL2) have been proposed as key actors. Congenital HYAL1 deficiency leads to mucopolysaccharidosis IX (MPS IX), a rare lysosomal storage disorder characterized by joint abnormalities. Knowledge of HYAL2 is limited. This protein displays weak in vitro hyaluronidase activity and acts as a receptor for oncogenic ovine retroviruses. We have generated HYAL2-deficient mice through a conditional Cre-lox system. Hyal2^–/– mice are viable and fertile. They exhibit localized congenital defects in frontonasal and vertebral bone formation and suffer from mild thrombocytopenia and chronic, possibly intravascular, hemolysis. In addition, Hyal2^–/– mice display 10-fold increases in plasma levels of HA and 2-fold increases in plasma hyaluronidase activity. Globally, there is no HA accumulation in tissues, including bones, but liver sinusoidal cells seem overloaded with undigested HA. Taken together, these elements demonstrate for the first time that murine HYAL2 has a physiological activity in vivo that is relevant for craniovertebral bone formation, maintenance of plasma HA concentrations, and erythrocyte and platelet homeostasis. In addition, the viability of HYAL2-deficient mice raises the possibility that a similar defect, defining a new MPS disorder, exists in humans.—Jadin, L., Wu, X., Ding, H., Frost, G. I., Onclinx, C., Triggs-Raine, B., Flamion, B. Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?

Key Words: hyaluronan • hyaluronidase • sinusoidal endothelial cells • hemolysis • frontonasal suture

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