Growth retardation occurs invariably in children with chronic renal failure; secondary hyperparathyroidism and tissue resistance to the actions of IGF-1 are major contributors to impaired growth. Calcitriol and recombinant human growth hormone are widely utilized to improve liner growth in children, but large intermittent doses of calcitriol have been shown to suppress bone formation and to induce adynamic lesions of bone; moreover, substantial reductions in linear growth have been reported during intermittent calcitriol therapy in children with renal therapy. These findings suggest that calcitriol can modify chondrocyte proliferation and/or differentiation in epiphyseal growth plate cartilage and may counteract the effect of recombinant human growth hormone to increase linear growth in children with chronic renal failure; the mechanisms responsible for these changes remain unknown. Parathyroid hormone related peptide (PTHrP) and the PTH/PTHrP receptor play critical roles in regulating chondrocyte differentiation in the epiphyseal growth plate, and PTH/PTHrP receptor expression is down- regulated in the growth plate cartilage of rats with renal failure; there is limited information, however, about the impact of renal bone disease per se or treatment with calcitriol or growth hormone is modifiers of the expression of PTH/PTHrP or other molecular markers of endochondral bone formation in renal failure. In the current project, chondrocyte proliferation will be assessed by bromodeoxyuridine (BrdU) incorporation and apoptosis of hypertrophic chondrocytes will be measured by the TUNEL assay in rats with renal failure and either secondary hyperparathyroidism or adynamic lesions of bone; the width of the growth plate will also be measured by quantitative histology. The technique of in situ hybridization will be used to quantify the expression of mRNAs for the PTH/PTHrP receptor, type II and type X collagen, alkaline phosphatase and IGF-1 in each disorder. The separate and combined effects of calcitriol and growth hormone on selected molecular markers on endochondral bone development will be examined in rats with adynamic renal bone disease, and the effect of continuous versus intermittent calcitriol therapy on the expression of these markers will be determined. The results of these studies will determine whether alterations in the regulation of chondrocyte proliferation and differentiation contribute to impaired linear growth in experimental renal failure and whether changes in the expression of known regulators of endochondral bone formation and chondrocyte differentiation account for these disturbances in vivo.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Hirschman, Gladys H
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University of Wisconsin Madison
Schools of Medicine
United States
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Sanchez, Cheryl P; He, Yu-Zhu (2009) Bone growth during rapamycin therapy in young rats. BMC Pediatr 9:3
Sanchez, C P; He, Y Z (2007) Bone growth during daily or intermittent calcitriol treatment during renal failure with advanced secondary hyperparathyroidism. Kidney Int 72:582-91
Sanchez, Cheryl P; He, Yu-Zhu (2005) Daily or intermittent calcitriol administration during growth hormone therapy in rats with renal failure and advanced secondary hyperparathyroidism. J Am Soc Nephrol 16:929-38
Sanchez, Cheryl P; He, Yu-Zhu (2004) Growth hormone therapy in calcium-loaded rats with renal failure. Endocrinology 145:3375-85
Sanchez, Cheryl P; He, Yu-Zhu; Leiferman, Ellen et al. (2004) Bone elongation in rats with renal failure and mild or advanced secondary hyperparathyroidism. Kidney Int 65:1740-8
Sanchez, Cheryl P (2003) Secondary hyperparathyroidism in children with chronic renal failure: pathogenesis and treatment. Paediatr Drugs 5:763-76
Sanchez, Cheryl P; He, Yu-Zhu (2003) Effects of thyroparathyroidectomy, exogenous calcium, and short-term calcitriol therapy on the growth plate in renal failure. J Am Soc Nephrol 14:148-58
Sanchez, Cheryl P; Kuizon, Beatriz D; Goodman, William G et al. (2002) Growth hormone and the skeleton in pediatric renal allograft recipients. Pediatr Nephrol 17:322-8
Sanchez, Cheryl P; He, Y-Z (2002) Alterations in the growth plate cartilage of rats with renal failure receiving corticosteroid therapy. Bone 30:692-8
Sanchez, C P (2001) Prevention and treatment of renal osteodystrophy in children with chronic renal insufficiency and end-stage renal disease. Semin Nephrol 21:441-50

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