Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Bone Biology

Increased glutamine catabolism mediates bone anabolism in response to WNT signaling

  • Text
  • PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts