mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy
Rosa Bartolomeo, … , Andrea Ballabio, Carmine Settembre
Rosa Bartolomeo, … , Andrea Ballabio, Carmine Settembre
Published September 5, 2017
Citation Information: J Clin Invest. 2017;127(10):3717-3729. https://doi.org/10.1172/JCI94130.
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Concise Communication Bone Biology Therapeutics

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance–associated gene (UVRAG), reducing the activity of the associated Beclin 1–Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1–Vps34–UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.

Authors

Rosa Bartolomeo, Laura Cinque, Chiara De Leonibus, Alison Forrester, Anna Chiara Salzano, Jlenia Monfregola, Emanuela De Gennaro, Edoardo Nusco, Isabella Azario, Carmela Lanzara, Marta Serafini, Beth Levine, Andrea Ballabio, Carmine Settembre

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Figure 6

Autophagy induction with Tat–Beclin 1 improves bone phenotype in MPS mice.

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Autophagy induction with Tat–Beclin 1 improves bone phenotype in MPS mic...
(A) Representative images of femoral growth plate sections from Gusb+/+, Gusb–/–, and Gusb–/– Tat–Beclin 1–treated mice (2 mg/kg daily for 15 d) immunostained with COL X and COL II. n = 3 mice per group. Scale bars: 100 μm. (B) Length of HZ. n = 3 mice per group. (C) Quantitative measurement of collagen isolated from the growth plates of mice treated as in A. n = 8. (D) Representative images of femurs and tibiae from P15 mice treated as in A. (E) Femur and tibia lengths. n = 8 mice per group. (F) Representative images of femurs and tibiae from Arsb+/+, Arsb–/–, and Arsb–/– Tat–Beclin 1–treated mice (2 mg/kg daily for 15 days). (G) Femur and tibia lengths. n = 6 mice per group. Data represent the mean values derived from the indicated number of mice. Error bars indicate the SEM. *P ≤ 0.05, **P ≤ 0.005, and ***P ≤ 0.0005, by ANOVA followed by Tukey’s post-hoc test.