Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate

• Published in: Kidney international Vol. 78; no. 6; pp. 561 - 568
• Main Authors: Álvarez-García, Óscar, García-López, Enrique, Loredo, Vanessa, Gil-Peña, Helena, Rodríguez-Suárez, Julián, Ordóñez, Flor Á., Carbajo-Pérez, Eduardo, Santos, Fernando
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01-09-2010; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; Animals, Newborn; Biological and medical sciences; children; Chondrocytes - pathology; Growth - drug effects; Growth Plate - drug effects; Growth Plate - growth & development; Immunosuppressive Agents - adverse effects; Insulin-Like Growth Factor I - analysis; Medical sciences; Neovascularization, Physiologic - drug effects; Nephrology. Urinary tract diseases; Osteoclasts - pathology; pediatric kidney transplantation; Rats; Receptor, IGF Type 1 - genetics; RNA, Messenger - analysis; Sirolimus - adverse effects; transplantation; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - analysis; Vascular Endothelial Growth Factor A - genetics; pediatric kidney transplantation; children; vascular endothelial growth factor; transplantation; Antineoplastic agent; Pediatrics; Endothelial cell; Nephrology; Sirolimus; Transplantation; vascalar endothelial growth factor; Kidney; Growth retardation; Urology; Macrocycle; Angiogenesis; Surgery; Graft; Protein synthesis inhibitor; Neovascularization; Child; Human; Lactone; Macrolide; Antibiotic; Epiphyseal cartilage; Treatment; Urinary system; Immunosuppressive agent; Antibacterial agent; Growth factor
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2010.173

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.