The Purinergic Nature of Pseudoxanthoma Elasticum

Simple Summary Pseudoxanthoma Elasticum (PXE) is an inherited disease that manifests in abnormal elastic fiber calcification in the eyes, the skin and the blood vessels. The gene responsible, called ABCC6, was identified in 2000 but it took nearly 15 years to understand how it works and how this gene's function relates to elastic fiber calcification. In essence, ABCC6 functions with at least two other enzymes (ENPP1 and CD73) to produce two inhibitors of calcification called pyrophosphate (PPi) and adenosine. In the absence of ABCC6, there is less PPi and adenosine produced, which leads to abnormal calcification in PXE patients. Remarkably, when ENPP1 or CD73 are mutated and non-functional this leads to other inherited diseases called General Arterial Calcification of Infancy (GACI) and Calcification of Joints and Arteries (CALJA), with overlapping symptoms. The three genes (ABCC6 -> ENPP1 -> CD73) normally work together to not only produce PPi, to prevent abnormal calcification, but also adenosine, which possesses numerous biological functions via a process called purinergic signaling. Our own work and a review of the scientific literature now indicate that PXE (and also GACI and CALJA) is an authentic "purinergic disease". In this article, we summarize the manifestations of PXE and review molecular and physiological data showing that PXE is indeed associated with a wide range of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease.Abstract Pseudoxanthoma Elasticum (PXE) is an inherited disease characterized by elastic fiber calcification in the eyes, the skin and the cardiovascular system. PXE results from mutations in ABCC6 that encodes an ABC transporter primarily expressed in the liver and kidneys. It took nearly 15 years after identifying the gene to better understand the etiology of PXE. ABCC6 function facilitates the efflux of ATP, which is sequentially hydrolyzed by the ectonucleotidases ENPP1 and CD73 into pyrophosphate (PPi) and adenosine, both inhibitors of calcification. PXE, together with General Arterial Calcification of Infancy (GACI caused by ENPP1 mutations) as well as Calcification of Joints and Arteries (CALJA caused by NT5E/CD73 mutations), forms a disease continuum with overlapping phenotypes and shares steps of the same molecular pathway. The explanation of these phenotypes place ABCC6 as an upstream regulator of a purinergic pathway (ABCC6 -> ENPP1 -> CD73 -> TNAP) that notably inhibits mineralization by maintaining a physiological Pi/PPi ratio in connective tissues. Based on a review of the literature and our recent experimental data, we suggest that PXE (and GACI/CALJA) be considered as an authentic "purinergic disease". In this article, we recapitulate the pathobiology of PXE and review molecular and physiological data showing that, beyond PPi deficiency and ectopic calcification, PXE is associated with wide and complex alterations of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease.