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

Abstract

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.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…27 Similarly, Hyal2-deficient mice have craniofacial anomalies reminiscent of those observed in the two patients we describe. 28 However, Cacna1h-deficient mice have no reported ptosis but rather cardiac fibrosis, which our two patients with CACNA1H homozygous truncation do not have. 29 Interestingly, heterozygous missense changes in CACNA1H have been associated with childhood epilepsy, but the two sisters we describe with a homozygous truncating mutation in this gene are completely normal neurologically except for ptosis.…”

Two Novel Functions of Hyaluronidase-2 (Hyal2) Are Formation of the Glycocalyx and Control of CD44-ERM Interactions

“…Hyaluronidase Activity-Both cell extracts and media were tested for hyaluronidase activity at different pH levels using zymography, which was performed as recently published by our group (7). In addition, 25-g protein samples from cell extracts were incubated in vitro with 15 g of 2.5 ϫ 10…”

“…Mice deficient in each of these genes have recently been described. However, Hyal3 knockout mice do not display a distinct phenotype (5), Hyal1 null animals develop a slowly progressive osteoarthritis without significant elevation of plasma or tissue levels of HA (6), and Hyal2 Ϫ/Ϫ mice show skeletal and hematological anomalies as well as 10-fold increases in plasma HA (7). Some of these apparent anomalies are explained perhaps by the non-enzymatic functions of these proteins.…”

Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis

“…All mice were age matched at adult age, and controls and Hyal-2 KO outbred 129P1.CD1 Hyal2 tm1.1BFla mice 28 (or c57Bl/6 background where indicated) were used. Mice were housed and bred in specific pathogen-free microisolator cages and fed standard Teklad irradiated chow in the Association for Assessment and Accreditation of Laboratory Animal Care Internationale certified Lerner Research Institute Biological Resource Unit.…”

“…28,29 Data from our laboratory and others indicate that MKs and platelets contain HA, but little is known about its role in these cells. 30,31 In addition, we found that both mouse and human MKs and platelets contain HYAL2 mRNA and protein with no evidence for HYAL1.…”