NDT Advance Access originally published online on June 28, 2005
Nephrology Dialysis Transplantation 2005 20(9):1904-1911; doi:10.1093/ndt/gfh876
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Downregulation of parathyroid hormone receptor gene expression and osteoblastic dysfunction associated with skeletal resistance to parathyroid hormone in a rat model of renal failure with low turnover bone
1 Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, 870-1201, 2 Kureha Special Laboratory Co., Ltd, Fukushima, 974-8232, 3 Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe, 650-0017 and 4 Institute of Medical Sciences, Tokai University School of Medicine, Kanagawa, 259-1193, Japan
Correspondence and offprint requests to: Masafumi Fukagawa, MD, PhD, Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe, 650-0017, Japan. Email: fukagawa{at}med.kobe-u.ac.jp
Background. Adynamic bone disease (ABD), which is characterized by reduced bone formation and resorption, has become an increasingly common manifestation of bone abnormalities in patients with end-stage renal failure. It has been recognized that skeletal resistance to parathyroid hormone (PTH) underlies the pathogenesis of ABD; however, the mechanisms of such resistance remain unclear.
Methods. We established a rat model simulating ABD under chronic renal failure conditions by thyroparathyroidectomy and partial nephrectomy (TPTx-Nx). TPTx-Nx rats were infused subcutaneously with a physiological dose of PTH. We analysed bone histomorphometric parameters and demonstrated gene expression using semi-quantitative reverse transcription–polymerase chain reaction.
Results. Reduced bone formation was observed in this model, simulating ABD. The reduction was dependent on the degree of renal dysfunction. Bone formation rate was 6.4±2.7 µm3/m2/year in TPTx-5/6Nx rats and 22.7±7.2 µm3/m2/year in TPTx rats (P<0.05). Osteoblast surface was also significantly depressed (P<0.05) in TPTx-5/6Nx (3.8±2.7%) compared with TPTx rats (15.9±8.6). The expression of PTH/parathyroid hormone-related peptide (PTHrP) receptor and alkaline phosphatase genes was reduced significantly in TPTx-Nx compared with TPTx rats (P<0.05). Reduced bone formation in TPTx-Nx rats was ameliorated by intermittent injection of pharmacological doses of PTH.
Conclusions. Renal dysfunction without secondary hyperparathyroidism induces osteoblast dysfunction and reduces bone formation. Skeletal resistance to PTH develops in renal failure even at low or normal PTH levels, possibly through downregulation of PTH/PTHrP receptor and dysfunction of osteoblasts.
Keywords: adynamic bone disease; animal model; bone histomorphometry; renal failure; skeletal resistance to parathyroid hormone
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