Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate

Abstract

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.

Growth of kidney-transplanted pediatric patients treated with sirolimus

“…However, experimental findings indicate that administration of SRL to fast-growing rats impairs longitudinal growth and induces marked alterations in growth-plate structure by mechanisms likely related to its inhibitory effects on cell proliferation and VEGF local expression [12][13][14].…”

Growth cartilage expression of growth hormone/insulin-like growth factor I axis in spontaneous and growth hormone induced catch-up growth

“…The hybridization procedure was carried out as described elsewhere [27]. Two parallel sections served as negative controls.…”

“…The dissection of growth plate was performed with magnifying lens and a scalpel to allow removing the adjacent bone zones accurately. The right tibiae were immediately frozen in liquid nitrogen for mRNA studies and the left tibiae were embedded in methylmethacrylate, fixed in 4% paraformaldehyde (PFA) and used for immunohistochemistry and in situ hybridization studies on growth plate as previously described [27][28][29].…”

“…Immunohistochemical staining was performed in PFA-fixed frontal sections (5 μm thick) of proximal tibiae, using IGF-I and IGF binding protein 5 (IGFBP5) polyclonal antibodies (Santa Cruz Biotechnology Inc, CA, USA) as described elsewhere [27].…”

CCAAT enhancer-binding proteins have long boney fingers

“…A downside could be the inhibition of normal bone growth and turnover by mTOR inhibition. Alvarez-Garcia et al [15] investigated the effects of rapamycin on longitudinal bone growth. They gave 4-week-old rats rapamycin daily for 2 weeks.…”