Weighing the Evidence for the Roles of Plasma Versus Local Pyrophosphate in Ectopic Calcification Disorders

Abstract

Ectopic calcification is characterized by inappropriate deposition of calcium mineral in nonskeletal connective tissues and can cause significant morbidity and mortality, particularly when it affects the cardiovascular system. Identification of the metabolic and genetic determinants of ectopic calcification could help distinguish individuals at the greatest risk of developing these pathological calcifications and could guide development of medical interventions. Inorganic pyrophosphate (PPi) has long been recognized as the most potent endogenous inhibitor of biomineralization. It has been intensively studied as both a marker and a potential therapeutic for ectopic calcification. Decreased extracellular concentrations of PPi have been proposed to be a unifying pathophysiological mechanism for disorders of ectopic calcification, both genetic and acquired. However, are reduced plasma concentrations of PPi a reliable predictor of ectopic calcification? This perspective article evaluates the literature in favor and against a pathophysiological role of plasma versus tissue PPi dysregulation as a determinant of, and as a biomarker for, ectopic calcification. © 2023 American Society for Bone and Mineral Research (ASBMR).

Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications

“…Unfortunately, our treatment approaches have not similarly advanced although there is hope. Novel therapies that extend the half-life of PPi or increase tissue activity are under development, offering hope for genetic disorders and severe calcification disorders such as calciphylaxis [257][258][259][260][261] and potentially for cardiovascular calcification. While the data strongly suggest vascular calcification confers substantial cardiovascular risk, due to a lack of therapeutics that directly modulate cardiovascular calcification in humans, the magnitude of risk reduction that would be achieved by preventing or reversing vascular calcification has yet to be definitively established.…”

Inorganic Pyrophosphate at Serum Concentration May Not Be Able to Inhibit Mineralization: A Study in Aqueous Solutions and Serum

“…The abnormalities in PPi-related biological molecules are associated with severe ectopic mineralization in vivo. For example, generalized arterial calcification of infancy (GACI) can be caused by a mutation of NPP1, which results in reduced enzyme activity of NPP1, decreased PPi production, and accumulation of mineralized and fragmented elastic fibers of the connective tissue in the skin. , Besides, inactivating mutations in ABCC6 usually result in pseudoxanthoma elasticum (PXE), an autosomal recessive disease in which circulating PPi is significantly reduced, leading to progressive ectopic mineralization of the matrix in the skin, eyes, and arteries. , …”

“…45,46 Besides, inactivating mutations in ABCC6 usually result in pseudoxanthoma elasticum (PXE), 47 an autosomal recessive disease in which circulating PPi is significantly reduced, leading to progressive ectopic mineralization of the matrix in the skin, eyes, and arteries. 45,46 However, it remains unclear how PPi plays a role in suppressing mineralization in serum. Considering that the serum concentration of PPi is as low as several μM, nearly 1000-fold lower than that of Pi as introduced above, it raises the question whether such trace amounts of PPi are effective in mineralization inhibition, especially when calcium and phosphorus concentrations in the physiological environment are abnormally elevated.…”

“… 45 , 46 Besides, inactivating mutations in ABCC6 usually result in pseudoxanthoma elasticum (PXE), 47 an autosomal recessive disease in which circulating PPi is significantly reduced, leading to progressive ectopic mineralization of the matrix in the skin, eyes, and arteries. 45 , 46 …”

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification

“…The ectopic calcification seen in PXE patients was initially thought to be a result of insufficient PPi generation in the circulation due to loss of ABCC6 in the liver [8]. As plasma PPi deficiency is considered a major determinant of ectopic calcification [12,13], therapies targeting the increase of PPi plasma concentrations have been shown to prevent the formation of these lesions in Abcc6 knockout murine models of PXE [14,15]. Etidronate (ETD), a stable PPi analog with anti-calcification properties, partially prevented ectopic calcification in Abcc6 knockout mice [16,17].…”