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Updated: Jun 23, 2026
A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
The effect of rapamycin on bone growth in rabbits
Chanika Phornphutkul1, Mark Lee, Cliff Voigt
1Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, Rhode Island Hospital and Brown University, Providence, RI 02903, USA. chanika_phornphutkul@brown.edu
Abstract:
mTOR is a nutrient-sensing protein kinase that regulates numerous cellular processes. Our prior studies using the mTOR inhibitor, rapamycin, indicate an important role for mTOR in chondrogenesis. We extended our observations to a physiological, in vivo model of bone growth, direct infusion of rapamycin into the proximal tibial growth plates of rabbits. Rapamycin or DMSO vehicle was infused directly into growth plates by an osmotic minipump for 8 weeks. Tibial growth was followed radiographically. At the end of the experiment, growth plates were recovered for histological analysis. Six animals were studied. No untoward effects of rapamycin infusion were found. Bone growth of limbs exposed to rapamycin was slower than control limbs, particularly during the period of most rapid growth. Histological analysis revealed that growth plate height in the rapamycin-infused limbs was reduced. Both the hypertrophic and proliferative zones were significantly smaller in the rapamycin-infused limbs. Direct infusion of rapamycin into proximal tibial growth plates decreased the size of the growth plate and inhibited overall long bone growth. Rapamycin appears to affect both the proliferative and hypertrophic zones of the tibial growth plate. Our results indicate that nutrients may exert a direct effect on long bone growth via mTOR-mediated modulation of chondrogenesis at the growth plate. and suggest that the possible inhibitory effects of rapamycin on skeletal growth warrant further attention before its use in children.
Insights
Rapamycin, an mTOR inhibitor, directly infused into rabbit growth plates slowed bone growth. This suggests nutrients impact long bone development via mTOR-mediated chondrogenesis, warranting caution before pediatric use.
Area of Science:
- Cellular Biology
- Developmental Biology
- Orthopedics
Background:
- Mammalian target of rapamycin (mTOR) is a key regulator of cellular processes, including chondrogenesis.
- Previous studies suggest mTOR plays a role in cartilage formation.
- Understanding mTOR's role in bone growth is crucial for pediatric skeletal development.
Purpose of the Study:
- To investigate the in vivo effect of direct mTOR inhibition on long bone growth.
- To determine the impact of rapamycin on chondrogenesis within the growth plate.
- To assess the influence of nutrient sensing pathways on skeletal development.
Main Methods:
- Direct infusion of rapamycin or vehicle control into rabbit proximal tibial growth plates via osmotic minipumps for 8 weeks.
- Radiographic monitoring of tibial growth throughout the study period.
- Histological analysis of growth plate tissues to evaluate cellular zones and overall structure.
Main Results:
- Direct rapamycin infusion into growth plates did not cause adverse effects.
- Rapamycin-treated limbs exhibited slower bone growth compared to controls, especially during peak growth periods.
- Histological analysis revealed reduced growth plate height, with significant decreases in both proliferative and hypertrophic zones.
Conclusions:
- Direct inhibition of mTOR in the growth plate via rapamycin reduces chondrogenesis and inhibits long bone growth.
- Nutrient availability may directly influence skeletal growth through mTOR-mediated pathways in chondrocytes.
- The potential inhibitory effects of rapamycin on skeletal growth necessitate careful consideration before its clinical application in children.
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