title: Bone growth during rapamycin therapy in young rats.
abstract: BACKGROUND
  Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties.
  
  
  METHODS
  Weanling three week old rats were given rapamycin at 2.5 mg/kg daily by gavage for 2 or 4 weeks and compared to a Control group given equivalent amount of saline. Morphometric measurements and biochemical determinations for serum calcium, phosphate, iPTH, urea nitrogen, creatinine and insulin-growth factor I (IGF-I) were obtained. Histomorphometric analysis of the growth plate cartilage, in-situ hybridization experiments and immunohistochemical studies for various proteins were performed to evaluate for chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption.
  
  
  RESULTS
  At the end of the 2 weeks, body and tibia length measurements were shorter after rapamycin therapy associated with an enlargement of the hypertrophic zone in the growth plate cartilage. There was a decrease in chondrocyte proliferation assessed by histone-4 and mammalian target of rapamycin (mTOR) expression. A reduction in parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) and an increase in Indian hedgehog (Ihh) expression may explain in part, the increase number of hypertrophic chondrocytes. The number of TRAP positive multinucleated chondro/osteoclasts declined in the chondro-osseous junction with a decrease in the receptor activator of nuclear factor kappa beta ligand (RANKL) and vascular endothelial growth factor (VEGF) expression. Although body and tibial length remained short after 4 weeks of rapamycin, changes in the expression of chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption which were significant after 2 weeks of rapamycin improved at the end of 4 weeks.
  
  
  CONCLUSIONS
  When given to young rats, 2 weeks of rapamycin significantly decreased endochondral bone growth. No catch-up growth was demonstrated at the end of 4 weeks, although markers of chondrocyte proliferation and differentiation improved. Clinical studies need to be done to evaluate these changes in growing children.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, USA. cpsanchez@pediatrics.wisc.edu
authors.forename: Cheryl P
authors.initials: CP
authors.lastname: Sanchez
authors.forename: Yu-Zhu
authors.initials: YZ
authors.lastname: He
mesh_terms: D000367:Age Factors; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus