Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate.
Rapamycin, a potent immunosuppressant used in renal transplantation, has been reported to impair longitudinal growth in experimental studies. Rapamycin is both antiproliferative and antiangiogenic; therefore, it has the potential to disrupt vascular endothelial growth factor (VEGF) action in the growth plate and to interfere with insulin-like growth factor I (IGF-I) signaling. To further investigate the mechanisms of rapamycin action on longitudinal growth, we gave the 4-week-old rats rapamycin daily for two weeks. Compared with a vehicle-treated group, rapamycin-treated animals were severely growth retarded and had marked alterations in the growth plate. Vascular invasion was disturbed in the rapamycin group, there was a significant reduction in osteoclast cells near the chondro-osseus junction, and there was lower VEGF protein and mRNA expression in the terminal chondrocytes of the growth cartilage. Compared with the control group, the rapamycin group had higher levels of circulating IGF-I as well as the mRNAs for IGF-I and of the receptors of IGF-I and growth hormone in the liver but not in the growth cartilage. Thus our findings explain the adverse effect of rapamycin on growth plate dynamics. This should be taken into account when the drug is administered to children.
Alvarez-García
Oscar
O
Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain.
García-López
Enrique
E
Loredo
Vanessa
V
Gil-Peña
Helena
H
Rodríguez-Suárez
Julián
J
Ordóñez
Flor A
FA
Carbajo-Pérez
Eduardo
E
Santos
Fernando
F
D000818:Animals; D000831:Animals, Newborn; D019902:Chondrocytes / Q000473:pathology; D006128:Growth / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects* / Q000254:growth & development; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010010:Osteoclasts / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics; D020123:Sirolimus / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020123:Sirolimus