Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?
Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?
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DOI：
10.1096/fj.08-111997
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Flamion, Bruno
中科院分区：
文献类型：
--
作者：
Jadin, Laurence;Wu, Xiaoli;Flamion, Bruno
透明质酸（HA）的代谢依赖于HA水解酶和透明质酸酶，其中透明质酸酶-1（HYAL 1）和-2（HYAL 2）已被认为是关键的参与者。先天性HYAL 1缺乏导致粘多糖沉积症IX（MPS IX），这是一种罕见的以关节异常为特征的溶酶体贮积症。对HYAL 2的了解有限。这种蛋白质在体外显示出弱的透明质酸酶活性，并作为致癌绵羊逆转录病毒的受体。我们通过条件性Cre-lox系统产生了HYAL 2缺陷小鼠。Hyal 2（-/-）小鼠存活且可生育。他们表现出局部先天性缺陷，在额鼻和脊椎骨形成，并患有轻度血小板减少症和慢性，可能是血管内，溶血。此外，Hyal 2（-/-）小鼠显示HA的血浆水平增加10倍，血浆透明质酸酶活性增加2倍。在全球范围内，组织（包括骨骼）中没有HA蓄积，但肝窦细胞似乎过载未消化的HA。总之，这些元素首次证明了鼠HYAL 2在体内具有与颅椎骨骨形成、维持血浆HA浓度以及红细胞和血小板稳态相关的生理活性。此外，HYAL 2缺陷小鼠的生存能力提高了人类存在类似缺陷的可能性，定义了一种新的MPS疾病。贾丁湖，Wu，X.，中国农业科学院，丁，H.，Frost，G.一、Onclinx，C.，Triggs-Raine，B.，火焰，B。HYAL 2缺陷小鼠的骨骼和血液学异常：第二类粘多糖沉积症IX？FASEB J. 22，4316-4326（2008）
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 cranio-vertebral 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? FASEB J. 22, 4316-4326 (2008)