Altered bone development and an increase in FGF-23 expression in Enpp1 -/- mice

Neil Charles Wallace Mackenzie, Dongxing Zhu, Elspeth M. Milne, Rob van't Hof, Aline Martin, Darryl Leigh Quarles, José Luis Millán, Colin Farquharson, Vicky Elisabeth MacRae

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Abstract

Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) is required for the conversion of extracellular ATP into inorganic pyrophosphate (PP i), a recognised inhibitor of hydroxyapatite (HA) crystal formation. A detailed phenotypic assessment of a mouse model lacking NPP1 (Enpp1 -/-) was completed to determine the role of NPP1 in skeletal and soft tissue mineralization in juvenile and adult mice. Histopathological assessment of Enpp1 -/- mice at 22 weeks of age revealed calcification in the aorta and kidney and ectopic cartilage formation in the joints and spine. Radiographic assessment of the hind-limb showed hyper-mineralization in the talocrural joint and hypo-mineralization in the femur and tibia. MicroCT analysis of the tibia and femur disclosed altered trabecular architecture and bone geometry at 6 and 22 weeks of age in Enpp1 -/- mice. Trabecular number, trabecular bone volume, structure model index, trabecular and cortical thickness were all significantly reduced in tibiae and femurs from Enpp1 -/- mice (P<0.05). Bone stiffness as determined by 3-point bending was significantly reduced in Enpp1 -/- tibiae and femurs from 22-week-old mice (P<0.05). Circulating phosphate and calcium levels were reduced (P<0.05) in the Enpp1 -/- null mice. Plasma levels of osteocalcin were significantly decreased at 6 weeks of age (P<0.05) in Enpp1 -/- mice, with no differences noted at 22 weeks of age. Plasma levels of CTx (Ratlaps™) and the phosphaturic hormone FGF-23 were significantly increased in the Enpp1 -/- mice at 22 weeks of age (P<0.05). Fgf-23 messenger RNA expression in cavarial osteoblasts was increased 12-fold in Enpp1 -/- mice compared to controls. These results indicate that Enpp1 -/- mice are characterized by severe disruption to the architecture and mineralization of long-bones, dysregulation of calcium/phosphate homeostasis and changes in Fgf-23 expression. We conclude that NPP1 is essential for normal bone development and control of physiological bone mineralization.

Original languageEnglish (US)
Article numbere32177
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 16 2012

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nucleotide pyrophosphatase
skeletal development
Bone Development
Bone
Phosphoric Diester Hydrolases
mice
pyrophosphatases
tibia
femur
Tibia
Femur
mineralization
nucleotides
bones
Physiologic Calcification
Plasmas
joints (animal)
Osteocalcin
Osteoblasts
Cartilage

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Mackenzie, N. C. W., Zhu, D., Milne, E. M., van't Hof, R., Martin, A., Quarles, D. L., ... MacRae, V. E. (2012). Altered bone development and an increase in FGF-23 expression in Enpp1 -/- mice. PLoS One, 7(2), [e32177]. https://doi.org/10.1371/journal.pone.0032177

Altered bone development and an increase in FGF-23 expression in Enpp1 -/- mice. / Mackenzie, Neil Charles Wallace; Zhu, Dongxing; Milne, Elspeth M.; van't Hof, Rob; Martin, Aline; Quarles, Darryl Leigh; Millán, José Luis; Farquharson, Colin; MacRae, Vicky Elisabeth.

In: PLoS One, Vol. 7, No. 2, e32177, 16.02.2012.

Research output: Contribution to journalArticle

Mackenzie, NCW, Zhu, D, Milne, EM, van't Hof, R, Martin, A, Quarles, DL, Millán, JL, Farquharson, C & MacRae, VE 2012, 'Altered bone development and an increase in FGF-23 expression in Enpp1 -/- mice', PLoS One, vol. 7, no. 2, e32177. https://doi.org/10.1371/journal.pone.0032177
Mackenzie, Neil Charles Wallace ; Zhu, Dongxing ; Milne, Elspeth M. ; van't Hof, Rob ; Martin, Aline ; Quarles, Darryl Leigh ; Millán, José Luis ; Farquharson, Colin ; MacRae, Vicky Elisabeth. / Altered bone development and an increase in FGF-23 expression in Enpp1 -/- mice. In: PLoS One. 2012 ; Vol. 7, No. 2.
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