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      Altered Bone Development and an Increase in FGF-23 Expression in Enpp1 −/− Mice

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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.

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          Most cited references60

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          Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.

          Patients with ESRD have a high circulating calcium (Ca) x phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vascular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesicles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhibitor fetuin-A and calcified minimally. Importantly, MV released under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pretreatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.
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            Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice.

            The osteoblast-specific secreted molecule osteocalcin behaves as a hormone regulating glucose metabolism and fat mass in two mutant mouse strains. Here, we ask two questions: is the action of osteocalcin on beta cells and adipocytes elicited by the same concentrations of the molecule, and more importantly, does osteocalcin regulate energy metabolism in WT mice? Cell-based assays using isolated pancreatic islets, a beta cell line, and primary adipocytes showed that picomolar amounts of osteocalcin are sufficient to regulate the expression of the insulin genes and beta cell proliferation markers, whereas nanomolar amounts affect adiponectin and Pgc1alpha expression in white and brown adipocytes, respectively. In vivo the same difference exists in osteocalcin's ability to regulate glucose metabolism on the one hand and affect insulin sensitivity and fat mass on the other hand. Furthermore, we show that long-term treatment of WT mice with osteocalcin can significantly weaken the deleterious effect on body mass and glucose metabolism of gold thioglucose-induced hyperphagia and high-fat diet. These results establish in WT mice the importance of this novel molecular player in the regulation of glucose metabolism and fat mass and suggest that osteocalcin may be of value in the treatment of metabolic diseases.
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              The parathyroid is a target organ for FGF23 in rats.

              Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                16 February 2012
                : 7
                : 2
                : e32177
                Affiliations
                [1 ]The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Midlothian, Scotland, United Kingdom
                [2 ]Rheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
                [3 ]Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America
                [4 ]University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
                University of Munich, Germany
                Author notes

                Conceived and designed the experiments: VEM CF JLM DLQ NCWM. Performed the experiments: NCWM DZ VEM AM EMM. Analyzed the data: NCWM DZ VEM RvH EMM. Contributed reagents/materials/analysis tools: NCWM DZ VEM JLM RvH EMM DLQ AM. Wrote the paper: NCWM VEM CF JLM DLQ.

                Article
                PONE-D-11-20040
                10.1371/journal.pone.0032177
                3281127
                22359666
                3a91a92a-570c-49dc-8cae-f1a2364efa56
                Mackenzie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 11 October 2011
                : 22 January 2012
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Endocrine System
                Musculoskeletal System
                Physiological Processes
                Developmental Biology
                Model Organisms
                Molecular Cell Biology

                Uncategorized
                Uncategorized

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