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.
Highlights
The chronic kidney disease associated mineral and bone disorder (CKD-MBD) is characterized by complex endocrine and metabolic disturbances, with a wide variability in terms of bone turnover, ranging from extremely low to extremely high bone formation rates [1]
We evaluated the effects of dietary phosphate on Adynamic Bone Disease (ABD) in rats with CKD and hypoparathyroidism
PTx resulted in blood ionized calcium (iCa) levels which were reduced by more than half, and was effective in preventing the usual CKD-associated hyperparathyroidism
Summary
The chronic kidney disease associated mineral and bone disorder (CKD-MBD) is characterized by complex endocrine and metabolic disturbances, with a wide variability in terms of bone turnover, ranging from extremely low to extremely high bone formation rates [1]. The hallmark of ABD is a decrease in bone turnover together with normal or low osteoid surface [1,6,7,8,9,10]. Resistance to parathyroid hormone (PTH) secondary to PTH receptor downregulation and decreased osteoblast number and activity are prevalent features. The latter results from reduced osteoblast proliferation and enhanced apoptosis, which are important factors in the determination of bone formation rates [11]. A clear understanding of the molecular mechanisms that lead to ABD, as well as the potential role of other bone cell types, in particular the osteocyte, is still lacking
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