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

Research output: Contribution to journalArticlepeer-review


Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) is required for the conversion of extracellular ATP into inorganic pyrophosphate (PPi), 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
Article numbere32177
JournalPLoS ONE
Issue number2
Publication statusPublished - Feb 2012


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