Role of CD73 and extracellular adenosine in disease

Purinergic Signalling

Simon C. Robson¹ 

[1] Harvard University$$

关键词: Tocris Bioscience;   

DOI  :  10.1007/s11302-011-9265-4

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

This landmark manuscript by St. Hillaire et al implicates CD73 in adult onset vascular calcification [1]. St. Hillaire and colleagues present translational work that identifies hitherto unknown recessive mutations in NT5E amongst patients with a shared phenotype, namely delayed vascular calcification. In a series of elegant experiments, they demonstrate a functional defect in CD73, recapitulate that defect by transferring the mutation in NT5E to previously unaffected cells and then repair the functional defect using both genetic rescue and by circumventing the pathway with exogenous adenosine.

Vascular calcification is known to be associated with an excess risk of cardiovascular events and has been linked to common, clinically important diseases such as diabetes and renal disease [2]. The role of purinergic signalling in the pathogenesis of vascular calcification was first suggested by the study of idiopathic infantile arterial calcification, an autosomal recessive disease caused by a loss-of-function mutation in the ectonucleotide pyrophosphatase–phosphodiesterase 1 gene (ENPP1), which generates pyrophosphate and AMP from ATP [3]. The published case series by St. Hillaire et al identifies nine persons from three families with calcifications of lower-extremity arteries and hand and foot joint capsules [1]. Each related a medical history and examination consistent with reduced peripheral blood flow manifested as pain with activity, also known as claudication. Imaging techniques confirmed the widespread, circumferential deposition of calcium along the (primarily infrarenal) peripheral arterial tree. Genomic analysis yielded a series of NT5E mutations each of which resulted in non-functional CD73. For example, the five affected members of family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662 C → A, p.S221X) in NT5E. Family 2’s affected members were homozygous for a missense mutation (p.C358Y) and the lone affected member of family 3 had one copy of NT5E with a frameshifted premature stop codon and one copy of p.C358Y. None of the heterozygous family members share the phenotype of vascular calcification. Cultured fibroblasts from affected members of “Family 1” show markedly reduced expression of NT5E messenger RNA, CD73 protein and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic-type “rescue” experiments normalized the CD73 and alkaline phosphatase activity in patients’ cells, and adenosine treatment decreased the levels of alkaline phosphatase and calcification.

【 授权许可】

Unknown