Abstract
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.
Highlights
ABCC6 facilitates the cellular efflux of ATP from liver and other tissues/cells, which is quickly converted to pyrophosphate (PPi), a potent inhibitor of mineralization
ABCC6 and NPP1 are functionally related proteins interchangeably causing Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) [17], we address some aspects of GACI and NPP1, which can be relevant for therapeutic interventions
Other than the cases associated with ENPP1 mutations [17], PXE manifestations can arise from multifactorial inheritance [58,59], environmental exposure [60,61,62,63] or secondary to β-thalassemia and sickle cell anemia [64]. β-thalassemia (MIM 141900) is a monogenic disorder caused by mutations in the β-globin gene that leads to the underproduction of β-globin chains
Summary
PXE, and GACI, and result from in a PPi production [18,19], is caused by increased. Been recently claimed by theinPi/PPi ratio in connective tissues It has been rethat ABCC6 acts downstream of NPP1 [20], this hypothesis is highly controversial in the cently claimed that ABCC6 acts downstream of NPP1 [20], this hypothesis is highly confield [21] and contradicts most studies [8,9,11,18]. 1) and the molecular cascade leading to PPi generation and TNAP inhibition offers many therapeutic interventions in the case of PXE and GACI. ABCC6 facilitates the cellular efflux of ATP from liver and other tissues/cells, which is quickly converted to pyrophosphate (PPi), a potent inhibitor of mineralization.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
