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.
Highlights
Rapamycin or sirolimus (Rapamune, Wyeth Pharmaceuticals, Philadelphia, PA, USA) is used as immunosuppressant in transplanted patients
This study shows for the first time that growth hormone (GH) administration increases longitudinal growth in young individuals treated with rapamycin at therapeutic doses
GH treatment caused a 20% increase in both growth velocity and nose to tail tip length in RGH animals when compared with rapamycin alone (RAPA) group
Summary
Rapamycin or sirolimus (Rapamune, Wyeth Pharmaceuticals, Philadelphia, PA, USA) is used as immunosuppressant in transplanted patients. On the basis of its potent immunosuppressive, antiproliferative and antitumor effects, rapamycin is able to treat multiple conditions simultaneously [2]. Experimental and clinical studies have showed that rapamycin is able to provide a low rate of acute rejection and a significant improvement in kidney allograft function, and to significantly decrease the incidence of posttransplant malignancies [3,4]. Rapamycin has the potential to interfere with fibrotic processes that often accompany transplant rejection and to influence the preferential development of immunological tolerance [2]. The use of rapamycin is associated with many side effects, including increases in serum cholesterol and triglycerides, anemia, proteinuria, skin rashes, retard of wound healing and diarrhea, which can eventually lead to rapamycin withdrawal [5]
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