title: Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy.
abstract: Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder of spontaneous infantile arterial and periarticular calcification which is attributed to mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) gene. Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation. In the present study, we used the Enpp1-/- mouse model of GACI to examine the effects of etidronate treatment (100 µg/kg), on vascular and skeletal calcification. Micro-computed tomography (µCT) analysis revealed a significant decrease in trabecular bone mass, as reflected by the decrease in trabecular bone volume/tissue volume (BV/TV; %), trabecular thickness, trabecular separation, trabecular number and pattern factor (P<0.05) in the Enpp1-/- mice in comparison to the wild-type (WT) mice. Mechanical testing revealed that in the WT mice, treatment with etidronate significantly improved work to fracture and increased work post-failure (P<0.05, in comparison to the vehicle-treated WT mice). This significant increase, however, was not observed in the Enpp1-/- mice. Treatment with etidronate had no effect on bone parameters in the WT mice; however, the Enpp1-/- mice displayed an increased structural model index (SMI; P<0.05). We used a recently developed 3D µCT protocol to reconstruct and quantify the extensive aortic calcification in Enpp1-/- mice in comparison to the WT mice. However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.
authors.affiliation: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Huesa
authors.affiliation: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Staines
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK.
authors.forename: Vicky E
authors.initials: VE
authors.lastname: MacRae
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002113:Calcification, Physiologic / Q000187:drug effects*; D004195:Disease Models, Animal; D012968:Etidronic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000097:blood; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011347:Procollagen / Q000097:blood; D011755:Pyrophosphatases / Q000235:genetics*; D061205:Vascular Calcification / Q000188:drug therapy* / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D010446:Peptide Fragments; D011347:Procollagen; C047202:procollagen Type I N-terminal peptide; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D012968:Etidronic Acid