Growth retardation occurs invariably in children with chronic renal failure; renal osteodystrophy and growth hormone resistance are considered to be major factors contributing to impaired skeletal growth. Calcitriol and recombinant human growth hormone (rhGH) are widely utilized to improve linear growth in these children. Although the bone trophic actions of rhGH differ substantially from the anti-proliferative effects of calcitriol on chondrocytes, there is limited information on the potential interactions between these two hormones on endochondral bone growth, particularly in pediatric patients with renal failure. Recent studies have demonstrated the critical roles of parathyroid hormone related protein (PTHrP), PTH/PTHrP receptor, and the Indian hedgehog (Ihh) in the regulation of endochondral bone formation; PTH/PTHrP receptor mRNA expression is downregulated in bone and kidney in uremic animals and this may be a potential mechanism contributing to decreased linear growth. It has not been studied in children with renal failure whether or not calcitriol and/or growth hormone modify the expression of these molecular markers. To determine the impact of chronic renal failure on endochondral bone development, selected molecular markers of chondrocyte differentiation will be evaluated in neonatal long bones implanted into adult mice with renal failure. The separate and combined effects of growth hormone and calcitriol on the selected markers of chondrocyte differentiation will also be assessed.
The specific aims of the current application are: 1) to utilize an established model of neonatal bone transplantation into adult murine recipients to characterize the effect of renal failure on chondrocyte differentiation and endochondral bone formation; 2) to characterize chondrocyte differentiation in epiphyseal growth plate cartilage by measuring the expression of selected molecular markers of endochondral bone formation including type II and type X collagen, PTHrP, PTH/PTHrP receptor and Ihh in subcutaneously implanted neonatal long bones; and 3) to determine whether calcitriol and/or growth hormone modify chondrocyte differentiation in animals with normal renal function and in those with chronic renal failure. The results of the proposed studies should provide new information to guide the development of more effective strategies for the prevention and management of growth retardation in children with chronic renal failure.
| Salusky, I B; Goodman, W G; Kuizon, B D (2000) Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism. Pediatr Nephrol 14:641-5 |
| Kuizon, B D; Salusky, I B (1999) Growth retardation in children with chronic renal failure. J Bone Miner Res 14:1680-90 |
