Cellular mechanisms of renal osteodystrophy.
Renal osteodystrophy affects all patients with end-stage renal failure, resulting in significant skeletal and extra-skeletal morbidity. The patterns of disease seen in bone are the result of changes in calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism, as well as the effects of uremia. Standard histological techniques, however, give little insight into the altered biological activity or mechanisms of disease at the cellular level. In order to examine the cellular abnormalities in renal bone disease we have performed a series of in situ hybridization studies to examine renal bone cell expression of genes for PTH receptor (PTHR1), transforming growth factor beta (TGF-beta) and insulin growth factor 1 (IGF-I). PTHR1 mRNA was expressed predominantly by osteoblasts, but also by resorbing osteoclasts, suggesting that these cells may be stimulated directly by PTH. Semi-quantitative analysis of gene expression showed down-regulation of PTHR1 mRNA by osteoblasts in renal bone compared with normal, fracture and Pagetic bone. This may be important in the pathogenesis of skeletal resistance seen in end-stage renal failure, altering the "threshold" at which PTH has its effects on bone cells. TGF-beta and IGF-I mRNA expression was also decreased, suggesting that synthesis of these factors, postulated to be mediators of PTH, is also downregulated.
Hoyland
J A
JA
Musculoskeletal Research Group, University of Manchester School of Medicine, United Kingdom. jhoyland@fs1.scg.man.ac.uk
Picton
M L
ML
D000818:Animals; D016723:Bone Remodeling; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000209:etiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology; D010281:Parathyroid Hormone / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018016:Receptors, Parathyroid Hormone; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I