Altered Bone Development and an Increase in FGF-23 Expression in Enpp12/2 Mice

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 (Enpp12/2) was completed to determine the role of NPP1 in skeletal and soft tissue mineralization in juvenile and adult mice. Histopathological assessment of Enpp12/2 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 Enpp12/2 mice. Trabecular number, trabecular bone volume, structure model index, trabecular and cortical thickness were all significantly reduced in tibiae and femurs from Enpp12/2mice (P,0.05). Bone stiffness as determined by 3-point bending was significantly reduced in Enpp12/2 tibiae and femurs from 22-week-old mice (P,0.05). Circulating phosphate and calcium levels were reduced (P,0.05) in the Enpp12/2 null mice. Plasma levels of osteocalcin were significantly decreased at 6 weeks of age (P,0.05) in Enpp12/2 mice, with no differences noted at 22 weeks of age. Plasma levels of CTx (RatlapsTM) and the phosphaturic hormone FGF-23 were significantly increased in the Enpp12/2 mice at 22 weeks of age (P,0.05). Fgf-23 messenger RNA expression in cavarial osteoblasts was increased 12-fold in Enpp12/2 mice compared to controls. Thes