Growth hormone improves growth retardation induced by rapamycin without blocking its antiproliferative and antiangiogenic effects on rat growth plate

PLoS One. 2012;7(4):e34788. doi: 10.1371/journal.pone.0034788. Epub 2012 Apr 6.

Abstract

Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Autophagy / drug effects
  • Cell Differentiation / drug effects
  • Child
  • Chondrocytes / drug effects*
  • Chondrocytes / metabolism
  • Chondrogenesis / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression / drug effects
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Growth Hormone / administration & dosage
  • Growth Hormone / therapeutic use*
  • Growth Plate / blood supply
  • Growth Plate / drug effects*
  • Growth Plate / growth & development
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Neovascularization, Physiologic / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Sirolimus / administration & dosage
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Antibiotics, Antineoplastic
  • beta Catenin
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • Sirolimus