Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure

Background. Resistance to the action of parathyroid hormone (PTH) has been demonstrated in end-stage renal failure and is considered to be important i n the pathogenesis of secondary hyperparathyroidism. The mechanism of resis tance is unknown. However, altered regulation of cellular PTH/PTH-related p rotein (PTH/PTHrP) receptor (PTH1R) has been assumed to be important. Methods. We have used in situ hybridization to examine PTH1R mRNA expressio n by osteoblasts in human bone and have compared the expression in high- an d low-turnover renal bone disease, high-turnover nonrenal bone disease (hea ling fracture callus and Pagetic bone), and normal bone. Bone biopsies were formalin fixed, ethylenediaminetetraacetic acid decalcified, and paraffin wax embedded. A 1.8 kb PTH1R cDNA probe, labeled with S-35, was used, and t he hybridization signal was revealed by autoradiography. The density of sig nal over osteoblasts was quantitated using a semiautomated Leica(TM) image analysis software package. Results. The mean density of PTH1R mRNA signal over osteoblasts in renal hi gh-turnover bone was only 36% of that found in nonrenal high-turnover bone (P < 0.05) and 51% of that found in normal bone (P < 0.05). Osteoblast PTH1 R mRNA signal in adynamic bone from individuals with diabetes mellitus was 28% of normal bone (P < 0.05) and 54% of that found in renal high-turnover bone (P < 0.05). Conclusions. These results demonstrate a down-regulation of osteoblast PTH1 R mRNA in end-stage renal failure in comparison to normal and high-turnover bone from otherwise healthy individuals, and provide an insight into the m echanisms of "skeletal resistance" to the actions of PTH.