Endocrinol Metab.  2018 Sep;33(3):318-330. 10.3803/EnM.2018.33.3.318.

Regulation of Osteoblast Metabolism by Wnt Signaling

• Moorer MC
• Riddle RC

• KMID: 2447021
• DOI: http://doi.org/10.3803/EnM.2018.33.3.318

Abstract

Wnt/β-catenin signaling plays a critical role in the achievement of peak bone mass, affecting the commitment of mesenchymal progenitors to the osteoblast lineage and the anabolic capacity of osteoblasts depositing bone matrix. Recent studies suggest that this evolutionarily-conserved, developmental pathway exerts its anabolic effects in part by coordinating osteoblast activity with intermediary metabolism. These findings are compatible with the cloning of the gene encoding the low-density lipoprotein related receptor-5 (LRP5) Wnt co-receptor from a diabetes-susceptibility locus and the now well-established linkage between Wnt signaling and metabolism. In this article, we provide an overview of the role of Wnt signaling in whole-body metabolism and review the literature regarding the impact of Wnt signaling on the osteoblast's utilization of three different energy sources: fatty acids, glucose, and glutamine. Special attention is devoted to the net effect of nutrient utilization and the mode of regulation by Wnt signaling. Mechanistic studies indicate that the utilization of each substrate is governed by a unique mechanism of control with β-catenin-dependent signaling regulating fatty acid β-oxidation, while glucose and glutamine utilization are β-catenin-independent and downstream of mammalian target of rapamycin complex 2 (mTORC2) and mammalian target of rapamycin complex 1 (mTORC1) activation, respectively. The emergence of these data has provided a new context for the mechanisms by which Wnt signaling influences bone development.

Keyword

Wnt signaling; Beta catenin; Osteoblasts; Intermediary metabolism

MeSH Terms

Anabolic Agents
beta Catenin
Bone Development
Bone Matrix
Clone Cells
Cloning, Organism
Fatty Acids
Glucose
Glutamine
Lipoproteins
Metabolism*
Osteoblasts*
Sirolimus
Anabolic Agents
Fatty Acids
Glucose
Glutamine
Lipoproteins
Sirolimus
beta Catenin

Figure

• 

  Fig. 1 Wnt signaling regulates the utilization of three fuel substrates by cells of the osteoblast lineage. Activation of Wnt signaling via the interaction of a Wnt ligand with a frizzled receptor (Fzd) and the low-density lipoprotein related receptor-5 (Lrp5) co-receptor inactivates the destruction complex consisting of disheveled (Dvl), Axin, glycogen synthase kinase-3β (Gsk3β), adenomatous polyposis coli (Apc), and casein kinase-1 (Ck-1). In mature osteoblasts, this allows the accumulation of β-catenin and its translocation to the nucleus, where the transcription factor activates the expression of genes involved in mitochondrial long-chain fatty acid oxidation. In osteoprogenitors, Wnt signaling activates mammalian target of rapamycin complex 1 (mTORC1) and mammalian target of rapamycin complex 2 (mTORC2) signaling to increase glutaminolysis and glycolysis, respectively. Wnt ligand binding inhibits Gsk3β activity and its ability to activate the tuberous sclerosis 1/2 (Tsc1/Tsc2) complex that inhibits mTORC1 activity. Activation of mTORC1 increases the abundance of glutaminase, the first enzyme in glutaminolysis. Activation of the mTORC2 complex, which regulates the abundance of proteins involved in glycolysis, is downstream of Rac family small GTPase 1 (Rac1). By inhibiting the entry of glucose into the tricarboxylic acid (TCA) cycle, Wnt regulates the availability of substrates for histone acetyltransferases. Red lines represent interactions that are suppressed by the activation of Wnt signaling, while green lines indicate interactions that are enhanced. mLST8, mammalian lethal with SEC13 protein 8; Sin1, stress activated protein kinase interacting protein 1.

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