Glucose metabolism induced by Bmp signaling is essential for murine skeletal development

Lee, Seung-Yon; Abel, E. Dale; Long, Fanxin

doi:10.1038/s41467-018-07316-5

Cited by 91 publications

(108 citation statements)

References 51 publications

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“…This may be explained by the short duration of Glut1 deficiency combined with a relatively low basal rate of bone formation, or due to potential compensatory mechanisms. Previously, deletion of Glut1 with Prx1-Cre had little impact on osteoblast differentiation in the mouse embryo even though the mineralizing activity appeared to be partially impaired (42). In vitro experiments in the current study showed that Glut1 deletion markedly reduced glucose metabolism by osteoblast lineage cells, thus arguing against functional compensation by the other glucose transporters.…”

Section: Discussionmentioning

confidence: 45%

Increased glycolysis mediates Wnt7b‐induced bone formation

Chen

Lee

et al. 2019

FASEB j.

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Wingless/integrated (Wnt) signaling has emerged as a major mechanism for promoting bone formation and a target pathway for developing bone anabolic agents against osteoporosis. However, the downstream events mediating the potential therapeutic effect of Wnt proteins are not fully understood. Previous studies have indicated that increased glycolysis is associated with osteoblast differentiation in response to Wnt signaling, but direct genetic evidence for the importance of glucose metabolism in Wnt‐induced bone formation is lacking. Here, we have generated compound transgenic mice to overexpress Wnt family member 7B (Wnt7b) transiently in the osteoblast lineage of postnatal mice, with or without concurrent deletion of the glucose transporter 1 (Glut1), also known as solute carrier family 2, facilitated glucose transporter member 1. Overexpression of Wnt7b in 1‐mo‐old mice for 1 wk markedly stimulated bone formation, but the effect was essentially abolished without Glut1, even though transient deletion of Glut1 itself did not affect normal bone accrual. Consistent with the in vivo results, Wnt7b increased Glut1 expression and glucose consumption in the primary culture of osteoblast lineage cells, and deletion of Glut1 diminished osteoblast differentiation in vitro. Thus, Wnt7b promotes bone formation in part through stimulating glucose metabolism in osteoblast lineage cells.—Chen, H., Ji, X., Lee, W.‐C., Shi, Y., Li, B., Abel, E. D., Jiang, D., Huang, W., Long, F. Increased glycolysis mediates Wnt7b‐induced bone formation. FASEB J. 33, 7810–7821 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 45%

Increased glycolysis mediates Wnt7b‐induced bone formation

Chen

Lee

et al. 2019

FASEB j.

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“…One interpretation of these results is that glucose metabolism is affected in the resident trabecular bone cells: the osteoblasts and osteoclasts. Although the effect of lactate accumulation in these cells has not been studied in detail, it is known that they rely on glucose uptake for cell differentiation and bone formation . In fact, recent studies showed that osteoblasts preferentially use glycolysis for ATP production, even under aerobic conditions, mimicking the Warburg effect .…”

Section: Discussionmentioning

confidence: 99%

“…Although the effect of lactate accumulation in these cells has not been studied in detail, it is known that they rely on glucose uptake for cell differentiation and bone formation. (50,72) In fact, recent studies showed that osteoblasts preferentially use glycolysis for ATP production, even under aerobic conditions, mimicking the Warburg effect. (73,74) It is therefore possible that loss of MCT4 may directly affect the metabolic profile of osteoblasts and interfere with proper trabecular bone formation and turnover in the vertebrae.…”

Section: Discussionmentioning

confidence: 99%

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Silagi

Novais

Bisetto

et al. 2019

Journal of Bone and Mineral Research

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Maintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H+/lactate concentrations are balanced by plasma‐membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complemented with genetic and metabolic approaches, we determine that H+/lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and tricarboxylic acid (TCA) cycle flux and intracellular pH homeostasis in the nucleus pulposus compartment of the disc, where hypoxia‐inducible factor 1α (HIF‐1α) directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful, disc degeneration. © 2019 American Society for Bone and Mineral Research.

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“…The compensatory upregulation of Tret1-1 transcription is independent of insulin/adipokinetic hormone signaling, but instead depends on TGF-β signaling. This regulatory mechanism that allows sparing the brain from the effects of malnutrition is likely conserved in mammals, since mammalian Glut1 is also upregulated in the BBB upon hypoglycemia and has been shown to be induced by TGF-β signaling in other tissues (Boado and Pardridge, 1993;Kumagai et al, 1995;Simpson et al, 1999;Lee et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

Hertenstein

McMullen²,

Weiler

et al. 2020

Preprint

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During hunger or malnutrition animals prioritize alimentation of the brain over other organs to ensure its function and thus their survival. This so-called brain sparing is described from Drosophila to humans. However, little is known about the molecular mechanisms adapting carbohydrate transport. Here, we used Drosophila genetics to unravel the mechanisms operating at the blood-brain barrier (BBB) under nutrient restriction. During starvation, expression of the carbohydrate transporter Tret1-1 is increased to provide more efficient carbohydrate uptake. Two mechanisms are responsible for this increase. Similarly to the regulation of mammalian GLUT4, Rab-dependent intracellular shuttling is needed for Tret1-1 integration into the plasma membrane, even though Tret1-1 regulation is independent of insulin signaling. In addition, starvation induces transcriptional upregulation controlled by TGF-β signaling. Considering TGF-β-dependent regulation of the glucose transporter GLUT1 in murine chondrocytes, our study reveals an evolutionarily conserved regulatory paradigm adapting the expression of sugar transporters at the BBB.

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Glucose metabolism induced by Bmp signaling is essential for murine skeletal development

Cited by 91 publications

References 51 publications

Increased glycolysis mediates Wnt7b‐induced bone formation

Increased glycolysis mediates Wnt7b‐induced bone formation

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

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