Wnt signaling and cellular metabolism in osteoblasts

Abstract

The adult human skeleton is a multifunctional organ undergoing continuous remodeling. Homeostasis of bone mass in a healthy adult requires an exquisite balance between bone resorption by osteoclasts and bone formation by osteoblasts; disturbance of such balance is the root cause for various bone disorders including osteoporosis. To develop effective and safe therapeutics to modulate bone formation, it is essential to elucidate the molecular mechanisms governing osteoblast differentiation and activity. Due to their specialized function in collagen synthesis and secretion, osteoblasts are expected to consume large amounts of nutrients. However, studies of bioenergetics and building blocks in osteoblasts have been lagging behind those of growth factors and transcription factors. Genetic studies in both humans and mice over the past 15 years have established Wnt signaling as a critical mechanism for stimulating osteoblast differentiation and activity. Importantly, recent studies have uncovered that Wnt signaling directly reprograms cellular metabolism by stimulating aerobic glycolysis, glutamine catabolism as well as fatty acid oxidation in osteoblast-lineage cells. Such findings therefore reveal an important regulatory axis between bone anabolic signals and cellular bioenergetics. A comprehensive understanding of osteoblast metabolism and its regulation is likely to reveal molecular targets for novel bone therapies.

Keywords: Bone; Fatty acids; Glucose; Glutamine; Metabolism; Osteoblast; Wnt; mTORC1; mTORC2.

Fig. 1

Wnt signaling promotes aerobic glycolysis through mTORC2 activation. Wnt signaling through Frizzled (Fz) and Lrp5/6 induces mTORC2 activity downstream of PI3K-Rac1 signaling whereas mTORC2 activation acutely increases the protein abundance of metabolic enzymes (in red) without changing their mRNA levels. Glc glucose, Glc-6-P glucose 6-phosphate, Fruc-6-P fructose 6-phosphate, Fruc-1,6-P fructose 1,6-bisphosphate, Pyr pyruvate, Lac lactate, Hk2 hexokinase 2, Pfk1 phosphofructokinase 1, Ldha lactate dehydrogenase A, Pdk1 pyruvate dehydrogenase kinase 1, PDC pyruvate dehydrogenase complex, TCA tricarboxylic acid cycle. See original reference for details [81]

Fig. 2

Wnt signaling stimulates glutamine catabolism through the TCA cycle. Wnt signaling through Frizzled (Fz) and Lrp5/6 activates mTORC1 in a PI3K-Akt dependent manner; mTORC1 increases the protein abundance of glutaminase (Gls) and stimulates glutamine oxidation for ATP production. The increase in glutamine consumption results in lower intracellular glutamine levels that activate the Gcn2-Atf4 stress pathway and up-regulate the transcription of genes important for protein translation. Gln glutamine, Glu glutamate, α-KG α-ketoglutarate. See original reference for details [76, 77]