Breaking up with glutamine
Dysfunctional osteoblast-driven bone development underlies many bone disorders. Osteoblast differentiation is critical for bone formation, and mature osteoblasts require an extensive amount of energy and increased translational capacity to support generation of the bone matrix. WNT-induced pathways are required for osteoblast differentiation; however, it is not clear how WNT signaling enables osteoblast progenitors to reconcile the energetic and translational needs required for proper differentiation. Courtney Karner and colleagues at Washington University examined osteoblast differentiation to examine how WNT signaling promotes efficient bone anabolism. In cultured osteoblast progenitors, WNT enhanced protein synthesis while decreasing glutamine levels. WNT activation increased both levels and activity of glutaminase, leading to increased glutamine utilization via the TCA cycle. The reduction in glutamine led to a GCN2-mediated integrated stress response, which activated genes that are important for protein synthesis, during osteoblast differentiation. Importantly, glutaminase inhibition by BPTES blocked WNT-induced glutamine consumption. In a murine model of hyperactive WNT signaling, genetic or pharmacologic depletion of GCN2 reduced trabecular bone mass and thickness, bone mineral density, mineral apposition, and formation rate. Together, these results suggest that targeting the glutamine/GCN2 pathway has therapeutic potential for bone disorders. The accompanying image shows Goldner trichome-stained femurs from WT mice (left), mice with hyperactive WNT signaling (middle), and mice lacking GCN2 with hyperactive WNT (right). Compared to WT animals, animals with hyperactive WNT have increased bone mineralization, an effect that is reduced in the absence of GCN2
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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
Authors
Courtney M. Karner, Emel Esen, Adewole L. Okunade, Bruce W. Patterson, Fanxin Long
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ISSN: 0021-9738 (print), 1558-8238 (online)