Lack of nucleotide pyrophosphatase phosphodiesterase1 activity in ENPP1-/- mice results in altered bone development and pathological mineralisation of soft tissue

Abstract

Event Abstract Back to Event Lack of nucleotide pyrophosphatase phosphodiesterase1 activity in ENPP1-/- mice results in altered bone development and pathological mineralisation of soft tissue NCW Mackenzie1*, D Zhu1, EM Milne1, JL Millan2, C Farquharson1 and VE Macrae1 1 University of Edinburgh, the Roslin Institute and Royal (Dick) School of Veterinary Studies, United Kingdom 2 Sanford-Burnam Medical Research Institute, United States Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) is required to convert extracellular ATP into inorganic pyrophosphate (PPi), a crucial negative regulator of hydroxyapatite (HA) crystal formation. NPP1, together with bone alkaline phosphatase, is responsible for maintaining the balance between PPi and inorganic phosphate (Pi) and thereby regulating the rate of HA formation in the developing skeleton. In this present study a detailed phenotypic assessment of a mouse model lacking NPP1 (Enpp1-/-) was carried out to further the understanding of its role in skeletal and soft tissue mineralisation. 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 evidence of hyper-mineralisation in the talocrural joint and hypo-mineralisation in the femur and tibia. Comprehensive microCT analysis of the tibia and femur examined the effects of Enpp1 ablation on trabecular architecture and bone geometry at 6 and 22 weeks of age in both male and female mice. Trabecular number, trabecular percentage bone volume, structure model index, trabecular and cortical thickness were significantly reduced (P<0.05) in tibiae and femurs from the Enpp1-/- mice compared to wild-type controls. This decreased bone mass was reflected by a significant reduction in maximum bone stiffness in Enpp1-/- tibiae and femurs from 22 week old mice (P<0.05) as determined by three-point bending. Circulating phosphate and calcium plasma levels were also reduced (P<0.05) in the Enpp1-/- null mice. Plasma levels of osteocalcin, a marker of bone formation, 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 (RatlapsTM ), a marker of bone resorption, and the phosphaturic hormone FGF-23 were significantly increased in the Enpp1-/- mice at 22 weeks of age (P<0.05). These results demonstrate that Enpp1-/- mice are characterised by severe disruption to the architecture and mineralisation of long-bones, dysregulation of calcium/phosphate homeostasis and hypercalcification in soft tissues. In summary, NPP1 is essential for normal bone development and the control of physiological bone mineralisation and pathological mineralisation in soft tissues. Keywords: Bones, Bone Research Conference: 2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society, Cambridge, United Kingdom, 27 Jun - 29 Jun, 2011. Presentation Type: Oral Topic: Abstracts Citation: Mackenzie N, Zhu D, Milne E, Millan J, Farquharson C and Macrae V (2011). Lack of nucleotide pyrophosphatase phosphodiesterase1 activity in ENPP1-/- mice results in altered bone development and pathological mineralisation of soft tissue. Front. Endocrinol. Conference Abstract: 2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society. doi: 10.3389/conf.fendo.2011.02.00041 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2011; Published Online: 30 Sep 2011. * Correspondence: Dr. NCW Mackenzie, University of Edinburgh, the Roslin Institute and Royal (Dick) School of Veterinary Studies, Roslin, United Kingdom, neil.mackenzie@roslin.ed.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers NCW Mackenzie D Zhu EM Milne JL Millan C Farquharson VE Macrae Google NCW Mackenzie D Zhu EM Milne JL Millan C Farquharson VE Macrae Google Scholar NCW Mackenzie D Zhu EM Milne JL Millan C Farquharson VE Macrae PubMed NCW Mackenzie D Zhu EM Milne JL Millan C Farquharson VE Macrae Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.