Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate

Area of Science:

• Pharmacology
• Developmental Biology
• Orthopedics

Background:

• Rapamycin is an immunosuppressant used in organ transplantation.
• Rapamycin's antiproliferative and antiangiogenic properties may affect longitudinal bone growth.
• Previous studies suggest rapamycin can impair growth, but mechanisms are unclear.

Purpose of the Study:

• To investigate the mechanisms by which rapamycin affects longitudinal bone growth.
• To examine rapamycin's impact on growth plate dynamics, vascular endothelial growth factor (VEGF), and insulin-like growth factor I (IGF-I) signaling.

Main Methods:

• Administered rapamycin or vehicle to 4-week-old rats daily for two weeks.
• Assessed growth retardation, growth plate morphology, and vascular invasion.
• Measured VEGF and IGF-I (and receptor) protein and mRNA expression in growth cartilage and liver.

Main Results:

• Rapamycin-treated rats exhibited severe growth retardation and altered growth plates.
• Disturbed vascular invasion and reduced osteoclast cells were observed in rapamycin-treated rats.
• Rapamycin reduced VEGF expression in growth cartilage but increased circulating IGF-I and related mRNA expression in the liver.

Conclusions:

• Rapamycin adversely affects growth plate dynamics by inhibiting VEGF signaling and altering IGF-I pathways.
• These findings elucidate the mechanisms behind rapamycin-induced growth impairment.
• Clinical consideration of rapamycin's impact on growth is crucial, especially in pediatric patients.