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Background: Fibroblast growth factor-23 (FGF-23) is a hormone principally produced by osteocytes/osteoblasts. In patients with chronic kidney disease (CKD), FGF-23 levels are usually elevated and can reach up to 300 – 400 times the normal range. FGF-23 is regulated by local bone-related and systemic factors, but the relationship between circulating FGF-23 concentrations and bone remodeling and mineralization in CKD has not been well characterized. In the current study, we examined the relationship between FGF-23 levels and bone histomorphometry parameters in adult patients with renal osteodystrophy. Material and methods: 36 patients on dialysis (CKD-5D) underwent bone biopsies after tetracycline double labeling. Blood drawings were done at time of biopsy to determine serum levels of markers of bone and mineral metabolism. Results: Patients with high bone turnover had higher values of serum FGF-23 than patients with low bone turnover. FGF-23 levels correlated with activation frequency (ρ = 0.60, p 100 days) was mainly seen in patients with FGF-23 levels less than 2,000 pg/mL, while very high levels of FGF-23 are associated with normal mineralization lag time.

BACKGROUND Soluble Klotho functions as an endocrine factor that plays important roles in a variety of pathophysiological processes. Soluble Klotho contains 130 KDa and 65 KDa isoforms. However, their distinct individual functional heterogeneity remains uncertain. Herein, we investigated the regulatory role of two soluble Klothos on cardiac fibrogenic responses. METHODS AND RESULTS The effect of soluble Klothos on myofibroblast differentiation, proliferation, and collagen synthesis/degradation were examined in cultured mouse cardiac myofibroblasts. The role of 130 KDa Klotho on fibrosis in hypertensive heart disease were examined in wild type (WT) and Klotho transgenic (Tg/+) mice receiving chronic angiotensin (Ang)II infusion. Our in vitro studies revealed that addition of 130 KDa soluble Klotho isoform increased collagen synthesis in a dose dependent manner. Furthermore, 130 KDa Klotho significantly stimulated myofibroblast differentiation, proliferation, and ERK phosphorylation, which were abolished by fibroblast growth factor (FGF) receptor antagonist (SU5402). In contrast, 65 KDa soluble Klotho treatment significantly suppressed myofibroblast proliferation and collagen synthesis. In vivo study further demonstrated that chronic AngII infusion lead to cardiac fibrosis in both WT and Tg/+ mice. However, cardiac collagen, TGF-β1, TIMP-2, and α-smooth muscle actin (SMA) levels were markedly upregulated in Tg/+ mice compared to WT cohort. CONCLUSION Taken together, these findings implicate that 130 KDa soluble Klotho plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway, whereas 65 KDa soluble Klotho exerts an anti-fibrotic effect in cardiac myofibroblasts. Thus, two distinct isoforms of soluble Klotho appear to play the counter-regulatory roles in cardiac fibrogenic responses.

Objective To demonstrate how expanding services covered by a “bundled payment” can also expand variation in the costs of treating patients under the bundle, using the Medicare dialysis program as an example. Data Sources/Study Setting Observational claims-based study of 197,332 Medicare hemodialysis beneficiaries enrolled for at least one quarter during 2006–2008. Study Design We estimated how resource utilization (all health services, dialysis-related services, and medications) changes with intensity of secondary hyperparathyroidism (sHPT) treatment. Data Extraction Methods Using Medicare claims, a patient-quarter level dataset was constructed, including a measure of sHPT treatment intensity. Principal Findings Under the existing, narrow dialysis bundle, utilization of covered services is relatively constant across treatment intensity groups; under a broader bundle, it rises more rapidly with treatment intensity. Conclusions The broader Medicare dialysis bundle reimburses providers uniformly, even though patients treated more intensively for sHPT cost more to treat. Absent any payment adjustments or efforts to ensure quality, this flat payment schedule may encourage providers to avoid high-intensity patients or reduce their treatment intensity. The first incentive harms efficiency. The second may improve or worsen efficiency, depending on whether it reduces appropriate or inappropriate treatment.

We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO(ob) osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (α-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in α-SMA(+) MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells.

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). Fgf23 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 longbones, 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. Citation: Mackenzie NCW, Zhu D, Milne EM, van ’t Hof R, Martin A, et al. (2012) Altered Bone Development and an Increase in FGF-23 Expression in Enpp1 Mice. PLoS ONE 7(2): e32177. doi:10.1371/journal.pone.0032177 Editor: Marlon R. Schneider, University of Munich, Germany Received October 11, 2011; Accepted January 22, 2012; Published February 16, 2012 Copyright: 2012 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. Funding: This work was supported by an Institute Strategic Programme Grant and Institute Career Path Fellowship funding from the Biotechnology and Biological Sciences Research Council (BBSRC; www.bbsrc.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. Competing Interests: The authors have declared that no competing interests exist. * E-mail: vicky.macrae@roslin.ed.ac.uk

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−/−Enpp1 tibiae and femurs from 22-week-old mice (P−/−Enpp1 null mice. Plasma levels of osteocalcin were significantly decreased at 6 weeks of age (P−/−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 (PFgf-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.

ObjectivesThe study objective was to assess the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use and mortality in patients with chronic kidney disease (CKD).BackgroundThere is insufficient evidence about the association of ACEI or ARBs with mortality in patients with CKD.MethodsA logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 U.S. veterans with nondialysis CKD who were previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses and in generalized linear models with binary outcomes and inverse probability of treatment weights in “as-treated” analyses.ResultsThe age of the patients at baseline was 75 ± 10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with a significantly lower risk of mortality both in the intention-to-treat analysis (hazard ratio: 0.81, 95% confidence interval: 0.78 to 0.84; p < 0.001) and the as-treated analysis with inverse probability of treatment weights (odds ratio: 0.37, 95% confidence interval: 0.34 to 0.41; p < 0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups.ConclusionsIn this large contemporary cohort of nondialysis-dependent patients with CKD, ACEI/ARB administration was associated with greater survival.