The effect of rapamycin on bone growth in rabbits

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. ß

Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

“…Although previous genetic and pharmacological studies have revealed the crucial role of mTORC1 in skeletal development (Chen and Long, 2014, Jiang et al., 2017, Phornphutkul et al., 2008, Phornphutkul et al., 2009, Yan et al., 2016), here we provide evidence demonstrating the critical role of the mTORC1/4E-BPs/SOX9 axis in skeletogenesis. Although it is well-established that Sox9 /SOX9 is the subject of many types of regulatory mechanisms, including epigenetic and transcriptional regulation of its gene, post-transcriptional regulation of its RNA, and post-translational modifications of its protein (Akiyama and Lefebvre, 2011, Kozhemyakina et al., 2015, Lefebvre and Dvir-Ginzberg, 2017), no previous literature has reported the translational control of Sox9 RNA thus far.…”

mTOR: A Potential Therapeutic Target in Osteoarthritis?

“…Direct infusion of rapamycin in growth plates by an osmotic minipump resulted in smaller hypertrophic and proliferative zones, decrease in the size of the growth plate, and inhibition of overall long bone growth in rabbits [58]. In young rats, treatment with rapamycin significantly decreased endochondral bone growth [59].…”

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

“…This potent inhibition of mTOR is likely to account for the cytostatic effects of BEZ235 on MSC growth observed at higher concentrations, given the well-established role of mTOR signaling in regulating protein synthesis. (52,53) To date, the role of mTOR in osteogenesis remains controversial because conflicting studies using rapamycin have reported both negative (54)(55)(56)(57)(58)(59) and positive (24)(25)(26) effects on osteogenesis.…”