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

Huesa C, Staines KA, Millán JL, MacRae VE - Int. J. Mol. Med. (2015)

Bottom Line: Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation.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.However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.

View Article: PubMed Central - PubMed

Affiliation: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK.

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.

No MeSH data available.


Related in: MedlinePlus

(A) Quantification (% of calcification) of calcium deposition in the aortae of 22-week-old Enpp1−/− mice. A standardised region of calcium deposition (400 slices from the subclavian artery) was selected and revealed no significant differences between the placebo (vehicle; saline)- and etidronate-treated groups. (B) Three-dimensional volumetric reconstructions of aortae from 22-week-old wild-type (WT) placebo-treated, WT etidronate-treated, Enpp1−/− placebo-treated, and Enpp1−/− etidronate-treated mice. Calcification is indicated by brown colouring. Bar represents 0.5 mm.
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f2-ijmm-36-01-0159: (A) Quantification (% of calcification) of calcium deposition in the aortae of 22-week-old Enpp1−/− mice. A standardised region of calcium deposition (400 slices from the subclavian artery) was selected and revealed no significant differences between the placebo (vehicle; saline)- and etidronate-treated groups. (B) Three-dimensional volumetric reconstructions of aortae from 22-week-old wild-type (WT) placebo-treated, WT etidronate-treated, Enpp1−/− placebo-treated, and Enpp1−/− etidronate-treated mice. Calcification is indicated by brown colouring. Bar represents 0.5 mm.

Mentions: We have previously demonstrated that Enpp1−/− mice exhibit arterial calcification from 11 weeks of age (31). In this study, we employed our recently developed three-dimensional (3D) µCT protocol (44) for the quantification of aortic calcification to examine the effects of treatment with etidronate on mice lacking Enpp1. As expected, the Enpp1−/− mice exhibited extensive aortic calcification in comparison to the WT mice at 22 weeks of age (Fig. 2B). However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta in these mice (Fig. 2).


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

Huesa C, Staines KA, Millán JL, MacRae VE - Int. J. Mol. Med. (2015)

(A) Quantification (% of calcification) of calcium deposition in the aortae of 22-week-old Enpp1−/− mice. A standardised region of calcium deposition (400 slices from the subclavian artery) was selected and revealed no significant differences between the placebo (vehicle; saline)- and etidronate-treated groups. (B) Three-dimensional volumetric reconstructions of aortae from 22-week-old wild-type (WT) placebo-treated, WT etidronate-treated, Enpp1−/− placebo-treated, and Enpp1−/− etidronate-treated mice. Calcification is indicated by brown colouring. Bar represents 0.5 mm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494596&req=5

f2-ijmm-36-01-0159: (A) Quantification (% of calcification) of calcium deposition in the aortae of 22-week-old Enpp1−/− mice. A standardised region of calcium deposition (400 slices from the subclavian artery) was selected and revealed no significant differences between the placebo (vehicle; saline)- and etidronate-treated groups. (B) Three-dimensional volumetric reconstructions of aortae from 22-week-old wild-type (WT) placebo-treated, WT etidronate-treated, Enpp1−/− placebo-treated, and Enpp1−/− etidronate-treated mice. Calcification is indicated by brown colouring. Bar represents 0.5 mm.
Mentions: We have previously demonstrated that Enpp1−/− mice exhibit arterial calcification from 11 weeks of age (31). In this study, we employed our recently developed three-dimensional (3D) µCT protocol (44) for the quantification of aortic calcification to examine the effects of treatment with etidronate on mice lacking Enpp1. As expected, the Enpp1−/− mice exhibited extensive aortic calcification in comparison to the WT mice at 22 weeks of age (Fig. 2B). However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta in these mice (Fig. 2).

Bottom Line: Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation.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.However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.

View Article: PubMed Central - PubMed

Affiliation: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK.

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.

No MeSH data available.


Related in: MedlinePlus