Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy

Carmen Huesa, Katherine A Staines, Jose Luis Millán, Vicky E MacRae

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)159-65
Number of pages7
JournalInternational Journal of Molecular Medicine
Volume36
Issue number1
DOIs
Publication statusPublished - Jul 2015
Externally publishedYes

Fingerprint

Etidronic Acid
Tomography
ectonucleotide pyrophosphatase phosphodiesterase 1
Arterial calcification of infancy
Vascular Calcification
Bone and Bones
Physiologic Calcification
Structural Models
Diphosphonates
Aorta

Keywords

  • Animals
  • Aorta
  • Bone Density
  • Bone Density Conservation Agents
  • Calcification, Physiologic
  • Disease Models, Animal
  • Etidronic Acid
  • Genetic Predisposition to Disease
  • Male
  • Mice
  • Mice, Knockout
  • Peptide Fragments
  • Phosphoric Diester Hydrolases
  • Procollagen
  • Pyrophosphatases
  • Vascular Calcification
  • X-Ray Microtomography
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Huesa, Carmen ; Staines, Katherine A ; Millán, Jose Luis ; MacRae, Vicky E. / Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy. In: International Journal of Molecular Medicine. 2015 ; Vol. 36, No. 1. pp. 159-65.
@article{3ac904f8e393453f941cb9f126058716,
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.",
keywords = "Animals, Aorta, Bone Density, Bone Density Conservation Agents, Calcification, Physiologic, Disease Models, Animal, Etidronic Acid, Genetic Predisposition to Disease, Male, Mice, Mice, Knockout, Peptide Fragments, Phosphoric Diester Hydrolases, Procollagen, Pyrophosphatases, Vascular Calcification, X-Ray Microtomography, Journal Article, Research Support, Non-U.S. Gov't",
author = "Carmen Huesa and Staines, {Katherine A} and Mill{\'a}n, {Jose Luis} and MacRae, {Vicky E}",
year = "2015",
month = "7",
doi = "10.3892/ijmm.2015.2212",
language = "English",
volume = "36",
pages = "159--65",
journal = "International Journal of Molecular Medicine",
issn = "1107-3756",
publisher = "Spandidos Publications",
number = "1",

}

Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy. / Huesa, Carmen; Staines, Katherine A; Millán, Jose Luis; MacRae, Vicky E.

In: International Journal of Molecular Medicine, Vol. 36, No. 1, 07.2015, p. 159-65.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy

AU - Huesa, Carmen

AU - Staines, Katherine A

AU - Millán, Jose Luis

AU - MacRae, Vicky E

PY - 2015/7

Y1 - 2015/7

N2 - 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.

AB - 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.

KW - Animals

KW - Aorta

KW - Bone Density

KW - Bone Density Conservation Agents

KW - Calcification, Physiologic

KW - Disease Models, Animal

KW - Etidronic Acid

KW - Genetic Predisposition to Disease

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Peptide Fragments

KW - Phosphoric Diester Hydrolases

KW - Procollagen

KW - Pyrophosphatases

KW - Vascular Calcification

KW - X-Ray Microtomography

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.3892/ijmm.2015.2212

DO - 10.3892/ijmm.2015.2212

M3 - Article

VL - 36

SP - 159

EP - 165

JO - International Journal of Molecular Medicine

JF - International Journal of Molecular Medicine

SN - 1107-3756

IS - 1

ER -