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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

Body weight of 11-week-old male Enpp1−/− and wild-type (WT) mice taken for 60 days from the day of administration of etidronate (day 0). Data are expressed as the means ± SEM.
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f1-ijmm-36-01-0159: Body weight of 11-week-old male Enpp1−/− and wild-type (WT) mice taken for 60 days from the day of administration of etidronate (day 0). Data are expressed as the means ± SEM.

Mentions: In initial experiments, we examined whether the treatment of Enpp1−/− and WT mice with 100 µg/kg etidronate affects their growth. In accordance with our previous study, the Enpp1−/− mice exhibited a reduced growth in comparison to the WT mice (18.4% smaller than the age-matched WT controls; P<0.05) (5). Intraperitoneal injections of etidronate had no effect on the total body weight of the WT mice, nor the Enpp1−/− mice in comparison to the respective vehicle-treated mice (Fig. 1). Notably, the Enpp1−/− mice appeared to lose weight from approximately 12 weeks of age, which may be a consequence of their limited movement due to excessive joint calcification (Fig. 1) (1,5).


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)

Body weight of 11-week-old male Enpp1−/− and wild-type (WT) mice taken for 60 days from the day of administration of etidronate (day 0). Data are expressed as the means ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijmm-36-01-0159: Body weight of 11-week-old male Enpp1−/− and wild-type (WT) mice taken for 60 days from the day of administration of etidronate (day 0). Data are expressed as the means ± SEM.
Mentions: In initial experiments, we examined whether the treatment of Enpp1−/− and WT mice with 100 µg/kg etidronate affects their growth. In accordance with our previous study, the Enpp1−/− mice exhibited a reduced growth in comparison to the WT mice (18.4% smaller than the age-matched WT controls; P<0.05) (5). Intraperitoneal injections of etidronate had no effect on the total body weight of the WT mice, nor the Enpp1−/− mice in comparison to the respective vehicle-treated mice (Fig. 1). Notably, the Enpp1−/− mice appeared to lose weight from approximately 12 weeks of age, which may be a consequence of their limited movement due to excessive joint calcification (Fig. 1) (1,5).

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