Effects of dietary phosphate on adynamic bone disease in rats with chronic kidney disease--role of sclerostin?

PLoS One. 2013 Nov 13;8(11):e79721. doi: 10.1371/journal.pone.0079721. eCollection 2013.

Abstract

High phosphate intake is known to aggravate renal osteodystrophy along various pathogenetic pathways. Recent studies have raised the possibility that dysregulation of the osteocyte Wnt/β-catenin signaling pathway is also involved in chronic kidney disease (CKD)-related bone disease. We investigated the role of dietary phosphate and its possible interaction with this pathway in an experimental model of adynamic bone disease (ABD) in association with CKD and hypoparathyroidism. Partial nephrectomy (Nx) and total parathyroidectomy (PTx) were performed in male Wistar rats. Control rats with normal kidney and parathyroid function underwent sham operations. Rats were divided into three groups and underwent pair-feeding for 8 weeks with diets containing either 0.6% or 1.2% phosphate: sham 0.6%, Nx+PTx 0.6%, and Nx+PTx 1.2%. In the two Nx+PTx groups, serum creatinine increased and blood ionized calcium decreased compared with sham control group. They also presented hyperphosphatemia and reduced serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels. Fractional urinary excretion of phosphate increased in Nx+PTx 1.2% rats despite lower PTH and FGF23 levels than in sham group. These biochemical changes were accompanied by a decrease in bone formation rates. The Nx+PTx 1.2% group had lower bone volume (BV/TV), higher osteoblast and osteocyte apoptosis, and higher SOST and Dickkopf-1 gene expression than the Nx+PTx 0.6% group. Nx+PTx 0.6% rat had very low serum sclerostin levels, and Nx+PTx 1.2% had intermediate sclerostin levels compared with sham group. Finally, there was a negative correlation between BV/TV and serum sclerostin. These results suggest that high dietary phosphate intake decreases bone volume in an experimental model of CKD-ABD, possibly via changes in SOST expression through a PTH-independent mechanism. These findings could have relevance for the clinical setting of CKD-ABD in patients who low turnover bone disease might be attenuated by optimal control of phosphate intake and/or absorption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Chemical Analysis
  • Body Weight
  • Bone Diseases / etiology*
  • Bone Diseases / metabolism*
  • Bone Morphogenetic Proteins / blood
  • Bone Morphogenetic Proteins / metabolism*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Disease Models, Animal
  • Gene Expression Profiling
  • Genetic Markers
  • Male
  • Osteoblasts / metabolism
  • Osteocytes / metabolism
  • Phosphates / metabolism
  • Phosphorus, Dietary / metabolism*
  • Rats
  • Renal Insufficiency, Chronic / complications*

Substances

  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Phosphates
  • Phosphorus, Dietary
  • Sost protein, rat

Grants and funding

This study was performed with grants from Fundação de Auxílio à Pesquisa do Estado de São Paulo (FAPESP, Grant 2008/58849-3) and Genzyme Co. Research in the laboratory of RMM is supported by CNPQ, Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant 303325/2010-0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.