mTOR signaling contributes to chondrocyte differentiation

Dev Dyn. 2008 Mar;237(3):702-12. doi: 10.1002/dvdy.21464.

Abstract

The mammalian Target Of Rapamycin (mTOR) is a nutrient-sensing protein kinase that regulates numerous cellular processes. Fetal rat metatarsal explants were used as a physiological model to study the effect of mTOR inhibition on chondrogenesis. Insulin significantly enhanced their growth. Rapamycin significantly diminished this response to insulin through a selective effect on the hypertrophic zone. Cell proliferation (bromodeoxyuridine incorporation) was unaffected by rapamycin. Similar observations were made when rapamycin was injected to embryonic day (E) 19 fetal rats in situ. In the ATDC5 chondrogenic cell line, rapamycin inhibited proteoglycan accumulation and collagen X expression. Rapamycin decreased content of Indian Hedgehog (Ihh), a regulator of chondrocyte differentiation. Addition of Ihh to culture medium reversed the effect of rapamycin. We conclude that modulation of mTOR signaling contributes to chondrocyte differentiation, perhaps through its ability to regulate Ihh. Our findings support the hypothesis that nutrients, acting through mTOR, directly influence chondrocyte differentiation and long bone growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Development
  • Bone and Bones / embryology
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Chondrocytes / cytology
  • Chondrocytes / metabolism*
  • Chondrogenesis* / drug effects
  • Growth Plate / embryology*
  • Growth Plate / metabolism
  • Hedgehog Proteins / metabolism*
  • Insulin / metabolism
  • Organ Culture Techniques
  • Protein Kinases / metabolism*
  • Rats
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Hedgehog Proteins
  • Insulin
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Sirolimus