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 fifteen 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.

Glucose metabolism in bone

“…2B). Besides PTH, the bone anabolic Wnt proteins also promote aerobic glycolysis in osteoblast lineage cells [34]. In particular, Wnt3a-Lrp5 signaling acutely increased the levels of Glut1, Hk2, Ldha and Pdk1 downstream of mTORC2 and Akt activation while inducing osteoblast differentiation from the bone marrow mesenchymal progenitor cell line ST2 [35] (Fig.…”

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

“…Bone cells produce many of the metabolic byproducts observed in active skeletal muscle (e.g., carbon dioxide, lactate, hydrogen ions, phosphate ions, adenosine diphosphate [ADP] and citric acid) (Borle et al 1960a; Karner 2016). For example, differentiating osteoblasts rely heavily upon glucose utilization (Esen et al 2013; Esen et al 2015) and produce lactate as a result (Felix et al 1978).…”

“…Yet during bone resorption, glycolysis is the predominant pathway (Lemma et al 2016). In addition, bone cells have the capacity to utilize amino and fatty acids (Karner 2016). Fatty acids undergo β-oxidation when they enter the cell, producing acetyl-coA for the tricarboxylic acid cycle (Karner 2016).…”

“…In addition, bone cells have the capacity to utilize amino and fatty acids (Karner 2016). Fatty acids undergo β-oxidation when they enter the cell, producing acetyl-coA for the tricarboxylic acid cycle (Karner 2016). Since metabolic activity is continual in bone and bone marrow cells, we must underscore how these factors released during cellular differentiation and bone formation and resorption contribute to the local regulation of bone blood flow.…”

Low Serum Levels of DKK2 Predict Incident Low‐Impact Fracture in Older Women

“…Recent studies show the importance of Wnt signaling to osteoblast differentiation . The most well‐studied secreted Wnt antagonists are sclerostin (SOST), dickkopfs (DKKs), and secreted frizzled related proteins (sFRPs), which regulate osteoblast‐mediated bone formation .…”