Abstract
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable disorders manifesting with ectopic tissue mineralization. Most cases of PXE and some cases of GACI are caused by mutations in the ABCC6 gene, resulting in reduced plasma pyrophosphate (PPi) levels. There is no effective treatment for these disorders. It has been suggested that administration of bisphosphonates, stable and non-hydrolyzable PPi analogs, could counteract ectopic mineralization in these disorders. In this study we tested the potential efficacy of etidronate, a first generation bisphosphonate, on ectopic mineralization in the muzzle skin of Abcc6−/− mice, a model of PXE. The Abcc6−/− mice received subcutaneous injections of etidronate, 0.283 and 3.40 mg/kg per injection (0.01× and 0.12×), twice a week, in both prevention and reversal studies. Ectopic mineralization in the dermal sheath of vibrissae in muzzle skin was determined by histopathologic analysis and by direct chemical assay for calcium content. Subcutaneous injection of etidronate prevented ectopic mineralization but did not reverse existing mineralization. The effect of etidronate was accompanied by alterations in the trabecular bone microarchitecture, determined by micro-computed tomography. The results suggest that etidronate may offer a potential treatment modality for PXE and GACI caused by ABCC6 mutations. Etidronate therapy should be initiated in PXE patients as soon as the diagnosis is made, with careful monitoring of potential side effects.
Highlights
Pseudoxanthoma elasticum (PXE), an autosomal recessive genodermatosis, is characterized by ectopic deposition of calcium hydroxyapatite in the skin, eyes, and the cardiovascular system, with considerable morbidity and occasional early mortality (For review see [1, 2])
We have previously shown that the mineralization of this dermal sheath is progressive and reflects the mineralization of arterial blood vessels, allowing us to monitor the temporal degree of mineralization in this mouse model by histopathology or direct chemical assay of calcium in biopsies of muzzle skin or by non-invasive microcomputed tomography [19, 20]
generalized arterial calcification of infancy (GACI) is clinically overlapping, yet more severe, ectopic mineralization disorder, the majority of patients dying from cardiovascular complications during their first year of life [23, 24]
Summary
Pseudoxanthoma elasticum (PXE), an autosomal recessive genodermatosis, is characterized by ectopic deposition of calcium hydroxyapatite in the skin, eyes, and the cardiovascular system, with considerable morbidity and occasional early mortality (For review see [1, 2]). ABCC6 encodes a transmembrane efflux transporter, ABCC6, expressed primarily in the liver, to a lesser extent in the kidneys, and at very low levels, if at all, in tissues subject to ectopic mineralization [5, 6]. These observations, together with results from animal studies, have suggested that PXE is a metabolic disorder deficient in circulating factor(s) required physiologically to prevent ectopic mineralization [7, 8]. Since PPi is physiologically a powerful anti-mineralization factor and proper PPi/Pi ratio in circulation is required to prevent ectopic mineralization, loss-of-function mutations in ABCC6 result in a reduced extracellular concentration of ATP and lowered PPi/Pi ratio, which allow ectopic mineralization to ensue in patients with PXE
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