Cellular mechanisms of renal osteodystrophy

Renal osteodystrophy affects all patients with end-stage renal failure, res ulting in significant skeletal and extra-skeletal morbidity. The patterns o f disease seen in bone are the result of changes in calcium, phosphate, par athyroid hormone (PTH), and vitamin D metabolism, as well as the effects of uremia. Standard histological techniques, however, give little insight int o 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 ren al bone cell expression of genes for PTH receptor (PTHR1), transforming gro wth factor beta (TGF-beta) and insulin growth factor 1 (IGF-I). PTHR1 mRNA was expressed predominantly by osteoblasts, but also by resorbing osteoclas ts, suggesting that these cells may be stimulated directly by PTH. Semi-qua ntitative analysis of gene expression showed downregulation of PTHR1 mRNA b y 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 effe cts on bone cells. TGF-beta and IGF-I mRNA expression was also decreased, s uggesting that synthesis of these factors, postulated to be mediators of PT H, is also downregulated.