Limits...
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

Serum marker analysis in Enpp1−/− and wild-type (WT) mice. (A) P1NP, a marker of bone formation; (B) CTx (RatLaps™), a marker of bone resorption. Results are expressed as the means ± SEM. *P<0.05; **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494596&req=5

f3-ijmm-36-01-0159: Serum marker analysis in Enpp1−/− and wild-type (WT) mice. (A) P1NP, a marker of bone formation; (B) CTx (RatLaps™), a marker of bone resorption. Results are expressed as the means ± SEM. *P<0.05; **P<0.01.

Mentions: The level of osteoblast and osteoclast activity was assessed by ELISA of serum taken from the etidronate-treated and vehicle-treated 22-week-old male Enpp1−/− and WT mice. The plasma concentrations of P1NP, a marker of bone formation, were unaltered in the Enpp1−/− and WT mice at 22 weeks of age (Fig. 3A). Moreover, no significant differences in bone formation were observed upon the administration of etidronate in the WT or Enpp1−/− mice (Fig. 3A). The plasma concentrations of CTx, a marker of bone resorption, were increased in the Enpp1−/− mice in comparison to the WT mice in both the etidronate- and vehicle-treated mice (P<0.05; Fig. 3B). This is in concordance with our previous observation of this marker in Enpp1−/− mice (5). However, there were no significant differences observed between the etidronate- and vehicle-treated mice in either parameter (Fig. 3).


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)

Serum marker analysis in Enpp1−/− and wild-type (WT) mice. (A) P1NP, a marker of bone formation; (B) CTx (RatLaps™), a marker of bone resorption. Results are expressed as the means ± SEM. *P<0.05; **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijmm-36-01-0159: Serum marker analysis in Enpp1−/− and wild-type (WT) mice. (A) P1NP, a marker of bone formation; (B) CTx (RatLaps™), a marker of bone resorption. Results are expressed as the means ± SEM. *P<0.05; **P<0.01.
Mentions: The level of osteoblast and osteoclast activity was assessed by ELISA of serum taken from the etidronate-treated and vehicle-treated 22-week-old male Enpp1−/− and WT mice. The plasma concentrations of P1NP, a marker of bone formation, were unaltered in the Enpp1−/− and WT mice at 22 weeks of age (Fig. 3A). Moreover, no significant differences in bone formation were observed upon the administration of etidronate in the WT or Enpp1−/− mice (Fig. 3A). The plasma concentrations of CTx, a marker of bone resorption, were increased in the Enpp1−/− mice in comparison to the WT mice in both the etidronate- and vehicle-treated mice (P<0.05; Fig. 3B). This is in concordance with our previous observation of this marker in Enpp1−/− mice (5). However, there were no significant differences observed between the etidronate- and vehicle-treated mice in either parameter (Fig. 3).

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