Abstract
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.
Highlights
Bone development and remodelling throughout life occurs through a tightly controlled balance of osteoblastic bone formation and resorption by osteoclasts
Enpp12/2 mice show reduced growth Initial studies addressed whether Enpp12/2 mice displayed a reduced growth phenotype resembling that previously reported for 10-day-old Enpp12/2 mice
At 6 weeks of age a significant reduction in body weight was observed in both male (83.7%; P,0.05) and female (87.7%; P,0.01) Enpp12/2 mice (Table 1)
Summary
Bone development and remodelling throughout life occurs through a tightly controlled balance of osteoblastic bone formation and resorption by osteoclasts. Bone formation during development and the remodeling cycle are a result of the secretion of proteins of the bone extracellular matrix (ECM), or osteoid and its mineralization in a two-stage process. Primary mineralization is a rapid phase where 70% of complete mineralization occurs. During the resorption phase of the remodeling cycle, osteoclasts through acid production and protease secretion induce demineralization and degradation of the bone matrix [1,2]. Mineralization is initiated within osteoblast- and chondrocytederived matrix vesicle (MVs) where Ca2+ ions and inorganic phosphate (Pi) crystallize to form hydroxyapatite (HA) [3].
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