WNT-LRP5 Signaling Induces Warburg Effect through mTORC2 Activation during Osteoblast Differentiation

Esen, Emel; Chen, Jianquan; Karner, Courtney M.; Okunade, Adewole L.; Patterson, Bruce W.; Long, Fanxin

doi:10.1016/j.cmet.2013.03.017

Cited by 306 publications

(327 citation statements)

References 60 publications

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“…Future studies are warranted to explore these potential mechanisms. Finally, in addition to hypoxia and HIFα stabilization, WNT signaling, a well-known mechanism for stimulating bone anabolism, also induces aerobic glycolysis during osteoblast differentiation (33). Thus, increased glycolysis may represent a general mechanism for osteoblast differentiation in response to various physiologic stimuli.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Regan¹,

Lim²,

Shi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The bone marrow environment is among the most hypoxic in the body, but how hypoxia affects bone formation is not known. Because low oxygen tension stabilizes hypoxia-inducible factor alpha (HIFα) proteins, we have investigated the effect of expressing a stabilized form of HIF1α in osteoblast precursors. Brief stabilization of HIF1α in SP7-positive cells in postnatal mice dramatically stimulated cancellous bone formation via marked expansion of the osteoblast population. Remarkably, concomitant deletion of vascular endothelial growth factor A (VEGFA) in the mouse did not diminish bone accrual caused by HIF1α stabilization. Thus, HIF1α-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1α stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1α-driven bone formation in vivo. Thus, HIF1α stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Regan¹,

Lim²,

Shi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

105

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“…A recent study (53) reported that Wnt-Lrp5 signaling also regulates glucose metabolism in osteoblasts. In this context, Wnt3a signaling through Lrp5 in cell lines characteristic of osteoprogenitors activated mTORC2-Akt signaling to increase the conversion of glucose to lactate via the Warburg effect.…”

Section: Discussionmentioning

confidence: 99%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

131

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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“…The molecular mechanism might not be through archetypal gene expression changes of a narrow set of target genes. Rather, Wnt signaling roles might promote, for example, a cellular metabolic state (Esen et al, 2013), or asymmetric cell divisions (Habib et al, 2013) that generally curtail differentiation. Regardless, the consequences of canonical Wnt inhibition on valve development highlight how both increased and decreased Wnt activity could cause various manifestations of congenital valve disease.…”

Section: Wnt Signaling and Developmental Transitions During Valvulogementioning

confidence: 99%

Wnt/β-catenin signaling enables developmental transitions during valvulogenesis

et al. 2016

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Heart valve development proceeds through coordinated steps by which endocardial cushions (ECs) form thin, elongated and stratified valves. Wnt signaling and its canonical effector β-catenin are proposed to contribute to endocardial-to-mesenchymal transformation (EMT) through postnatal steps of valvulogenesis. However, genetic redundancy and lethality have made it challenging to define specific roles of the canonical Wnt pathway at different stages of valve formation. We developed a transgenic mouse system that provides spatiotemporal inhibition of Wnt/β-catenin signaling by chemically inducible overexpression of Dkk1. Unexpectedly, this approach indicates canonical Wnt signaling is required for EMT in the proximal outflow tract (pOFT) but not atrioventricular canal (AVC) cushions. Furthermore, Wnt indirectly promotes pOFT EMT through its earlier activity in neighboring myocardial cells or their progenitors. Subsequently, Wnt/β-catenin signaling is activated in cushion mesenchymal cells where it supports FGF-driven expansion of ECs and then AVC valve extracellular matrix patterning. Mice lacking Axin2, a negative Wnt regulator, have larger valves, suggesting that accumulating Axin2 in maturing valves represents negative feedback that restrains tissue overgrowth rather than simply reporting Wnt activity. Disruption of these Wnt/β-catenin signaling roles that enable developmental transitions during valvulogenesis could account for common congenital valve defects.

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WNT-LRP5 Signaling Induces Warburg Effect through mTORC2 Activation during Osteoblast Differentiation

Cited by 306 publications

References 60 publications

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Wnt/β-catenin signaling enables developmental transitions during valvulogenesis

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