Abstract
Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Here, we report that although the mechanistic target of rapamycin complex 1 (mTORC1) activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation. Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation programme within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice. Rapamycin promotes chondrocyte differentiation and restores these defects in mutant mice. Mechanistically, mTORC1 downstream kinase S6K1 interacts with and phosphorylates Gli2, and releases Gli2 from SuFu binding, resulting in nuclear translocation of Gli2 and transcription of parathyroid hormone-related peptide (PTHrP), a key regulator of bone development. Our findings demonstrate that dynamically controlled mTORC1 activity is crucial to coordinate chondrocyte proliferation and differentiation partially through regulating Gli2/PTHrP during endochondral bone development.
Highlights
Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms
Our findings show that activation of Gli[2] by mechanistic target of rapamycin complex 1 (mTORC1) is required for parathyroid hormone-related peptide (PTHrP) transcription and that dynamic regulation of mTORC1 activity is crucial to coordinate chondrocyte growth, proliferation and differentiation during endochondral bone development
To investigate the role of mTORC1 in chondrocyte proliferation and differentiation, we initially examined its activity in the growth plate of developing long bones
Summary
Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Endochondral bone formation depends on a highly coordinated programme of proliferation, differentiation and maturation through permanent withdrawal from the cell cycle, hypertrophy and terminal differentiation of chondrocytes within the mammalian growth plate. The invading vasculature triggers resorption of hypertrophic cartilage matrix and formation of the bone marrow cavity, and recruits osteoblast and osteoclast precursors that produce cancellous bone within the marrow cavity, and cartilage is eventually replaced by mineralized bone deposits[14,15,16] This programme is regulated by a complex network of molecules, including Indian hedgehog (IHH), parathyroid hormone-related peptide (PTHrP), bone morphogenetic proteins, fibroblast growth factors and the respective receptors, and interactions between cells and the extracellular matrix[17,18,19]. Our findings show that activation of Gli[2] by mTORC1 is required for PTHrP transcription and that dynamic regulation of mTORC1 activity is crucial to coordinate chondrocyte growth, proliferation and differentiation during endochondral bone development
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