PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats.

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats. Growth retardation, hypocalcaemia, hyperphosphataemia, and skeletal resistance to the action of PTH are well known features of advanced chronic renal failure (CRF). It has been suggested that the downregulation of renal and skeletal PTH receptors (PTH/PTHrP-R) could play an important role in the occurrence of these abnormalities. In the present study, four uraemic (4 weeks after 5/6 nephrectomy) and four control (sham-operated) rats were analysed for PTH/PTHrP-R mRNA expression at the proximal femoral and tibial growth plates by in situ hybridization. Uraemic rats had plasma biochemical abnormalities of advanced CRF including high creatinine, phosphate, and PTH, and low calcium and calcitriol levels. The femoral and tibial bones of uraemic animals were shorter in length than those of control rats, and had reduced width and cellularity of the epiphyseal cartilage growth plate. Mean (+/- SD) tibia growth plate width was 152 +/- 30 microns in uraemic rats, compared with 170 +/- 35 microns in control rats. The difference was mostly due to a marked reduction of the zone expressing PTH/PTHrP-R (mature chondrocytes) which was 30 +/- 5 microns in tibias from uraemic versus 44 +/- 10 microns in tibias from control rats. The hybridization signals of PTH/PTHrP-R per individual cell were quantified on dark field images using a computer-assisted image analysis system. The number of grains in PTH/PTHrP-R positive cells was also decreased in uraemic rats, 103 +/- 13 compared with 123 +/- 14 arbitrary units (dark pixel density)/cell in control rats (P < 0.005). In conclusion, these data indicate that rats with severe CRF and secondary hyperparathyroidism have reduced epiphyseal cartilage PTH/PTHrP-R mRNA expression. This alteration may be relevant in the pathogenesis of growth retardation in uraemia.