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

• Published in: Nephrology, dialysis, transplantation Vol. 20; no. 9; pp. 1904 - 1911
• Main Authors: Iwasaki-Ishizuka, Yoshiko, Yamato, Hideyuki, Nii-Kono, Tomoko, Kurokawa, Kiyoshi, Fukagawa, Masafumi
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2005; Oxford Publishing Limited (England)
• Subjects: Actins - blood; adynamic bone disease; Alkaline Phosphatase - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; animal model; Animals; Base Sequence; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; bone histomorphometry; Disease Models, Animal; DNA Primers; Drug Resistance; Emergency and intensive care: renal failure. Dialysis management; Infusions, Intravenous; Injections, Subcutaneous; Intensive care medicine; Kidney Failure, Chronic - complications; Male; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Osteoblasts - pathology; Parathyroid Hormone - administration & dosage; Parathyroid Hormone - therapeutic use; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptor, Parathyroid Hormone, Type 1 - genetics; Renal failure; skeletal resistance to parathyroid hormone; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Thyroxine - administration & dosage; Thyroxine - pharmacology; Kidney disease; Animal model; Urinary system disease; Rat; Hemodialysis; skeletal resistance to parathyroid hormone; Rodentia; Diseases of the osteoarticular system; Bone disease; Gene expression; Extrarenal dialysis; Vertebrata; Mammalia; bone histomorphometry; Parathyroid hormone; Animal; Renal failure; Turnover; adynamic bone disease
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfh876

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.