title: The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene.
abstract: Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable ectopic mineralization disorders. Most cases of PXE and many cases of GACI harbor mutations in the ABCC6 gene. There is no effective treatment for these disorders. We explored the potential efficacy of bisphosphonates to prevent ectopic calcification caused by ABCC6 mutations by feeding Abcc6(-/-) mice with diet containing etidronate disodium (ETD) or alendronate sodium trihydrate (AST) in quantities corresponding to 1x, 5x, or 12x of the doses used to treat osteoporosis in humans. The mice were placed on diet at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks by quantitation of the calcium deposits in the dermal sheath of vibrissae, a progressive biomarker of the mineralization, by computerized morphometry of histopathologic sections and by direct chemical assay of calcium. We found that ETD, but not AST, at the 12x dosage, significantly reduced mineralization, suggesting that selected bisphosphonates may be helpful for prevention of mineral deposits in PXE and GACI caused by mutations in the ABCC6 gene, when combined with careful monitoring of efficacy and potential side-effects.
authors.affiliation: a Department of Dermatology and Cutaneous Biology; Sidney Kimmel Medical College ; Thomas Jefferson University ; Philadelphia , PA USA.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
authors.forename: Sharon F
authors.initials: SF
authors.lastname: Terry
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019386:Alendronate / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D012968:Etidronic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation; D011561:Pseudoxanthoma Elasticum / Q000188:drug therapy* / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D061205:Vascular Calcification / Q000188:drug therapy* / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D019386:Alendronate; D050071:Bone Density Conservation Agents; D012968:Etidronic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse
keywords: AST, alendronate sodium trihydrate; ETD, etidronate disodium; GACI, generalized arterial calcification of infancy; KO, knock-out; PXE, pseudoxanthoma elasticum; WT, wild-type; bisphosphonates; ectopic mineralization; generalized arterial calcification of infancy; pseudoxanthoma elasticum