Increased glutamine catabolism mediates bone anabolism in response to WNT signaling

J Clin Invest. 2015 Feb;125(2):551-62. doi: 10.1172/JCI78470. Epub 2014 Dec 22.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Citric Acid Cycle*
  • Gene Deletion
  • Glutamine / genetics
  • Glutamine / metabolism*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Osteogenesis*
  • Osteosclerosis / genetics
  • Osteosclerosis / metabolism*
  • Osteosclerosis / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Transfer, Amino Acyl / genetics
  • RNA, Transfer, Amino Acyl / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Wnt Signaling Pathway*

Substances

  • Multiprotein Complexes
  • RNA, Transfer, Amino Acyl
  • Glutamine
  • TOR Serine-Threonine Kinases
  • EIF2AK4 protein, human
  • Eif2ak4 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases