Increased glutamine catabolism mediates bone anabolism in response to WNT signaling
Courtney M. Karner, … , Bruce W. Patterson, Fanxin Long
Courtney M. Karner, … , Bruce W. Patterson, Fanxin Long
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):551-562. https://doi.org/10.1172/JCI78470.
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Research Article Bone Biology

Increased glutamine catabolism mediates bone anabolism in response to WNT signaling

Abstract

WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2–mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were β-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases.

Authors

Courtney M. Karner, Emel Esen, Adewole L. Okunade, Bruce W. Patterson, Fanxin Long

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Figure 1

WNT/mTORC1-dependent protein synthesis induces a transient energy deficit during osteoblast differentiation.

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WNT/mTORC1-dependent protein synthesis induces a transient energy defici...
(A) Effect of Torin1 on WNT-induced mTORC1 signaling and AMPK phosphorylation assayed by Western blot. Phospho-proteins normalized to respective total protein. Fold change ± SD for WNT3A over vehicle in 3 independent experiments. (B and C) Metabolic labeling of protein synthesis in response to WNT3A (B) and the effect of Torin1 (C). Cyclohexamide (Chx) used to inhibit protein synthesis as a control in B. Error bars indicate SD. *P < 0.05, Student’s t test. n = 3. (D) Effect of WNT3A on AMPK phosphorylation at 1, 6, and 12 hours. Fold change ± SD from 3 independent experiments.