Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel

Abstract

Artery calcification reflects an admixture of factors such as ectopic osteochondral differentiation with primary host pathological conditions. We review how genetic factors, as identified by human genome-wide association studies, and incomplete correlations with various mouse studies, including knockout and strain analyses, fit into "pieces of the puzzle" in intimal calcification in human atherosclerosis, and artery tunica media calcification in aging, diabetes mellitus, and chronic kidney disease. We also describe in sharp contrast how ENPP1, CD73, and ABCC6 serve as "cogs in a wheel" of arterial calcification. Specifically, each is a minor component in the function of a much larger network of factors that exert balanced effects to promote and suppress arterial calcification. For the network to normally suppress spontaneous arterial calcification, the "cogs" ENPP1, CD73, and ABCC6 must be present and in working order. Monogenic ENPP1, CD73, and ABCC6 deficiencies each drive a molecular pathophysiology of closely related but phenotypically different diseases (generalized arterial calcification of infancy (GACI), pseudoxanthoma elasticum (PXE) and arterial calcification caused by CD73 deficiency (ACDC)), in which premature onset arterial calcification is a prominent but not the sole feature.

Figure 1. Pieces of the “puzzle”: Host, environmental, and genetic factors contributing to human arterial calcification

Although the inhibitory role of some of the specific factors with regard to arterial calcification has been proven, others may have promoting or direct or indirect “regulatory” effects. Some of the factors, including COMP and TGM2, are not explicitly discussed in the text.

Figure 2. Typical manifestations of generalized arterial calcification of infancy (GACI) caused by mutations in ENPP1

A, Cardiac ultrasound (suprasternal long-axis view) of a 4-week-old boy; note increased echogenicity of the wall of the ascending aorta (arrow-heads). B, Radiograph of the left hand of a 2-week-old boy showing periarticular calcifications (arrow). C, Cross section of the left coronary artery from a boy who died of myocardial infarction at the age of 9 weeks, showing calcification at the level of the internal elastic lamina (arrows) and intimal proliferation (hematoxylin and eosin staining). Ao indicates aorta, LA; left atrium.

Figure 3. Model of an SMC functional network revealed by 3 human monogenic diseases of artery calcification (GACI due to ENPP1 deficiency, PXE due to ABCC6 deficiency, and ACDC due to CD73 deficiency)

This review describes how ENPP1, CD73, and ABCC6 serve as “cogs in a wheel.” Specifically, each is a minor component in the function of a much larger network of factors, illustrated here, that exert balanced effects to promote and suppress arterial calcification. For the network to normally suppress spontaneous arterial calcification, the “cogs,” ENPP1, CD73, and ABCC6, must be present and in working order. Monogenic ENPP1, CD73, and ABCC6 deficiencies each drive a molecular pathophysiology of closely related but phenotypically different diseases (GACI, ACDC, and PXE, respectively), in which premature onset arterial calcification is a prominent but not sole feature. The transmembrane ectoenzyme ENPP1 generates AMP and PP_i from ATP, which are hydrolyzed by the GPI-linked ecto-enzymes CD73 (5′exonucleotidase) and TNAP, to generate adenosine and PP_i, respectively. PP_i suppresses hydroxyapatite deposition and inhibits ectopic chondrogenesis (and modulates artery calcification by other effects). ENPP1 modulates RAGE expression, as discussed in the text, and PP_i limits promineralizing type I collagen. The PP_i transporter ANKH, as well as ENPP1, elevates extracellular PP_i, and murine deficiency of this transporter is associated with arterial calcification, driven in part by vanin-1 pantetheinase expression, which depresses cellular GSH stores and promotes ectopic chondrogenesis. Adenosine signaling suppresses TNAP expression and inhibits vascular inflammation and neointima formation. ABCC6 has been hypothesized, though not yet proven, to modulate adenosine transport. P_i signals, in part through uptake, mediated the Na⁺-dependent P_i cotransporter to promote osteochondral differentiation, and P_i is a component of hydroxyapatite crystal deposition. In addition, systemic effects of hepatic ABCC6 deficiency, including circulating fetuin deficiency, appear to modulate arterial and skin features of PXE (illustration credit: Cosmocyte/Ben Smith).