Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum ( Abcc6 -/- )

• Published in: Oncotarget Vol. 9; no. 56; pp. 30721 - 30730
• Main Authors: Li, Qiaoli, Kingman, Joshua, Sundberg, John P, Levine, Michael A, Uitto, Jouni
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.07.2018
• Subjects: Research Paper; bisphosphonates; etidronate treatment; mouse model; pseudoxanthoma elasticum; ectopic mineralization
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10738

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 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 mice, a model of PXE. The 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 mutations. Etidronate therapy should be initiated in PXE patients as soon as the diagnosis is made, with careful monitoring of potential side effects.