Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation

Abstract

Significance The transition from a mitotic to a postmitotic, hypertrophic chondrocyte is a key regulatory event in the growing vertebrate skeleton. By using genetic approaches, cell culture, and cell transplantation models, we provide compelling evidence that attenuating the energy-sensing mammalian target of rapamycin complex 1 (mTORC1) pathway is critical for switching chondrocyte states. A failure of mTORC1 suppression in Lkb1 mutants leads to a dramatic disruption of the skeletal growth plate and the formation of cartilage tumors comprising undifferentiated chondrocytes that display differential sensitivity to two key cartilage growth regulators, Indian hedgehog and Igf. The study highlights the interconnection between energy sensing pathways, normal growth control, and tumorigenesis in the skeletal program.

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