mTOR signaling contributes to chondrocyte differentiation

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. Developmental Dynamics 237:702-712, 2008.

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…[41][42][43] However, in this study, we did not observe frequent activation of mTOR in tumors of smooth muscle cell, adipocyte, or chondrocyte origin in contrast to rhabdomyosarcoma. Probably, the functional involvement of mTOR is different in tumor vs normal tissue, or the involvement of mTOR in those tumors may be transient in the specific stage during oncogenesis.…”

Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

“…Infection of chondrocytes with lentivirus expressing CA MEK reduced both aggrecan mRNA expression and proteoglycan protein synthesis, as did activation of MEK-ERK using tBHP. Negative regulation of proteoglycan production by activated MEK-ERK has been previously observed during chondrogenesis in embryonic chick limb bud cultures (50), and inhibition of MEK-ERK has been found to promote chondrocytic differentiation of ATDC5 cells (51) and aggrecan expression in immortalized rat chondrocytes (52). These findings are in contrast to a study of mechanically stimulated bovine calf chondrocytes, where inhibition of MEK-ERK either reduced aggrecan expression or had no effect, depending on the stimulation conditions (53).…”

Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

“…Rapamycin, an MTOR inhibitor, decreases longitudinal bone growth and chondrocyte hypertrophy. 11,12 Thus, it is plausible to assume that activation of MTORC1 leads to increased chondrocyte hypertrophy and bone growth. Supporting this we found that the MTOR inhibitor Torin1 attenuates Baf-and CQ-induced bone growth.…”

“…10 Rapamycin, an MTOR inhibitor which mainly disrupts MTORC1 activity, 1 inhibits bone growth both in vitro and in vivo. 11,12 Conditional ablation of RPTOR in the limb (using periaxin [Prx]-driven Cre) reduces limb size and hypertrophic chondrocyte cell size. 13 Furthermore, MTORC1 was proposed to regulate the transition of chondrocytes from the proliferative to the post-mitotic stage of maturation.…”