Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development

Abstract

Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multisystem clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI), characterized by severe, early-onset mineralization of the cardiovascular system, often with early postnatal demise. In addition, arterial calcification due to CD73 deficiency (ACDC) occurs late in life, mostly affecting arteries in the lower extremities in elderly individuals. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6, ENPP1, and NT5E, respectively, are characterized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Because PPi is a powerful antimineralization factor, it has been postulated that reduced PPi is a major determinant for ectopic mineralization in these conditions. These and related observations on complementary mechanisms of ectopic mineralization have resulted in development of potential treatment modalities for PXE, including administration of bisphosphonates, stable PPi analogs with antimineralization activity. It is conceivable that efficient treatments may soon become available for heritable ectopic mineralization disorders with application to common calcification disorders.

Figure 1

Clinical features and histopathology of ectopic mineralization in pseudoxanthoma elasticum (PXE). A: Characteristic early cutaneous signs of PXE consist of discrete yellowish papules at predilection sites, such as sides of the neck. B: These early lesions coalesce into plaques of inelastic, leathery skin. C: Histopathology of the affected area of skin reveals accumulation of pleiomorphic elastotic material in the mid dermis, as visualized by Verhoeff–van Gieson stain. D: Staining of a parallel section with von Kossa stain reveals mineralization of the elastotic structures. E: Characteristic ocular findings consist of angioid streaks, breaks in the Bruch membrane behind the retina (arrows), which allow neovascularization (arrowheads) of the retina, leading to loss of visual acuity and blindness. F: Histopathology of the left renal artery in a generalized arterial calcification of infancy patient with ABCC6 mutations reveals extensive mineralization (hematoxylin-eosin stain).

Figure 2

Different pathomechanisms controlling ectopic mineralization. Hyperphosphatemic familial tumoral calcinosis (HFTC) is associated with altered Pi homeostasis (marked hyperphosphatemia) because of mutations in one of the three proteins involved in the regulation of inorganic phosphate (Pi) excretion in the kidney (GALNT3, FGF23, and KLOTHO). Normophosphatemic familial tumoral calcinosis (NFTC) is caused by mutations in the SAMD9 gene with unknown function in prevention of ectopic mineralization without altered serum phosphate levels. ATP-binding cassette, subfamily C, member 6 (ABCC6), ectonucleotide pyrophosphotase/phosphodiesterase 1 (ENPP1), and 5’-ecto nucleotidase (CD73) are plasma membrane–associated proteins controlling the synthesis and degradation of inorganic pyrophosphate (PPi). ENPP1 is the principal enzyme that generates PPi from ATP hydrolysis. ABCC6 works upstream of ENPP1 by mediating release of ATP, a substrate for ENPP1. CD73 cleaves AMP to adenosine and Pi, with adenosine being an inhibitor of tissue nonspecific alkaline phosphatase (TNAP), which degrades PPi. Mutations in these proteins result in pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and arterial calcification due to deficiency of CD73 (ACDC), respectively, all characterized by reduced plasma PPi levels. Loss-of-function mutations in the gene encoding TNAP, which degrades PPi to Pi, result in hypophosphatasia (HOPS) attributable to increased plasma PPi levels. Adapted with permission from Uitto et al. EC, extracellular; IC, intracellular.

Figure 3

Treatment of Abcc6^−/− mice, a model of pseudoxanthoma elasticum, with etidronate, a bisphosphonate analog of inorganic pyrophosphate (PPi), prevents ectopic mineralization. A: Bisphosphonates (BPs) are stable analogs of PPi because of the presence of a carbon bond, instead of oxygen, and the presence of side chains (R1 and R2). B: Top left panel:Abcc6^−/− mice at 12 weeks of age demonstrate extensive mineralization of the connective sheath of vibrissae in the muzzle skin, as demonstrated by Alizarin Red stain. Administration of etidronate either orally (p.o.; top middle panel) or by s.c. injections (top right panel) during weeks 4 to 12 significantly reduced the mineral deposits. Administration of etidronate also significantly increased the density of trabecular bone both in male (middle row) and in female (bottom row) mice.