ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

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.

The Interplay Between Brain Vascular Calcification and Microglia

“…Analysis of mineral phases on calcified aortas of MGP-deficient mice ( Mgp –/– ) using various spectroscopic and microscopic techniques suggest that calcification of elastin in the absence of MGP is reminiscent of multistep bone mineralization via amorphous calcium phosphate precursors to crystalline structures (hydroxyapatite) ( Gourgas et al, 2018 ). Analysis of Abcc6 and Nt5e knockout mice and mice lacking functional ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has led to the hypothesis that reduced plasma PPi, an inhibitor of calcium phosphate crystal growth, leads to a pro-mineralizing environment ( Shimada et al, 2021 ). ABCC6 (ATP-binding cassette subfamily C member 6) facilitates cellular ATP efflux and the cascade of extracellular ATP degradation to adenosine involves hydrolyzes ATP to AMP and PPi by ENPP1.…”

Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches

“…Among this class of compounds, especially interesting are β,γ-modified nucleotides, such as bisphosphonates [39,40], hypophosphates [41] and ATP derivatives, which may be hydrolyzed by ectonucleotidases with the release of modified pyrophosphate analogues. TNAP is considered as a potential target for anti-calcification drug design [4]. Due to its role in brain microvascular dysfunction and neuroinflammation in late sepsis [3], it seems to also be a good target for such disorders.…”

“…The presence of this enzyme has been detected in numerous tissues, including the kidney, liver and bones, as well as the central nervous system [2,3]. Numerous studies indicate its involvement in calcification disorders [4], neuronal development, synaptic function [5], interactions within the brain-immune axis [3,6], thermogenesis [1] and cancer.…”

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors

“…Regarding ectopic calcification, it is important to note that the biochemical reactions behind this process appear to be much more complex than what can be expressed by a simple index, such as the serum calcium x phosphate product [ 35 ]. Other chemical mediators likely play a significant role, with pyrophosphate levels possibly modulating calcium deposition [ 36 ]. Circulating pyrophosphate, a natural inhibitor of hydroxyapatite formation, is usually removed by phosphatases.…”