Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation

Lee, Seung-Yon; Long, Fanxin

doi:10.1172/jci96221

Cited by 85 publications

(63 citation statements)

References 43 publications

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“…Indeed, upon Notch2 activation, NICD forms a transcriptional complex and induces transcriptional activation of as of yet unidentified repressors that decrease the expression of both glycolytic enzymes and mitochondrial respiration proteins. Additionally, NICD-mediated suppression of the reactive oxygen species-producing mitochondrial complex-1 led to a reduction in AMPK activity and further suppression of glycolysis in ST2 cells 147 . Finally, evidence suggests that PTH inhibits Notch signalling in osteoblast-and osteocyte-enriched cultures, which raises the possibility that these two pathways might coordinately influence osteoblast metabolism 148 .…”

Section: Control Of Osteoblast Glucose Usage Bymentioning

confidence: 97%

“…The function of Notch in bone is evidenced by studies showing that the conditional deletion of the receptor Notch2 in early mesenchymal progenitor cells using the Prx-Cre driver strain results in increased bone mass 145 while sustained activation of Notch2 signaling in osteoblasts induces osteopenia in mice 146 . It was proposed that one of the mechanisms by which Notch exerts its effects on bone is through the suppression of glycolysis in early osteolineage cells and a subsequent reduction in osteoblast differentiation 147 . Indeed, upon Notch2 activation, NICD forms a transcriptional complex and induces transcriptional activation of as of yet unidentified repressors that decrease the expression of both glycolytic enzymes and mitochondrial respiration proteins.…”

Section: Control Of Osteoblast Glucose Usage Bymentioning

confidence: 99%

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The role of osteoblasts in energy homeostasis

et al. 2019

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Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with osteoclasts, which resorb bone, in a continuous cycle that occurs throughout life. The unique function of osteoblasts requires substantial amounts of energy production, particularly during states of new bone formation and remodeling. Over the last 15 years, studies have shown that osteoblasts secrete endocrine factors that integrate the metabolic requirements of bone formation with global energy balance through the regulation of insulin production, feeding behavior, and adipose tissue metabolism. In this article, we summarize the current understanding of three osteoblast-derived metabolic hormones (osteocalcin, lipocalin and sclerostin) and the clinical evidence that suggests the relevance of these pathways in humans, while also discussing the necessity of specific energy substrates (glucose, fatty acids and amino acids) to fuel bone formation and promote osteoblast differentiation.

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Section: Control Of Osteoblast Glucose Usage Bymentioning

confidence: 97%

Section: Control Of Osteoblast Glucose Usage Bymentioning

confidence: 99%

The role of osteoblasts in energy homeostasis

et al. 2019

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“…Recent studies have shown several interesting mechanistic aspects of Notch function in modulating osteoblast differentiation. Notch signaling may lead to the suppression of glucose metabolism restricting osteoblast differentiation in mesenchymal progenitors [78]. Another study showed a functional link between Notch signaling and mechanotransduction in which Notch serves as a mediator in response to mechanical strain in mesenchymal cells [79].…”

Section: Notch Regulation Of Osteoblast Differentiation and Osteocytementioning

confidence: 99%

Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis

et al. 2020

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Skeletal development is a complex process which requires the tight regulation of gene activation and suppression in response to local signaling pathways. Among these pathways, Notch signaling is implicated in governing cell fate determination, proliferation, differentiation and apoptosis of skeletal cells-osteoblasts, osteoclasts, osteocytes and chondrocytes. Moreover, human genetic mutations in Notch components emphasize the critical roles of Notch signaling in skeletal development and homeostasis. In this review, we focus on the physiological roles of Notch signaling in skeletogenesis, postnatal bone and cartilage homeostasis and fracture repair. We also discuss the pathological gain- and loss-of-function of Notch signaling in bone and cartilage, resulting in osteosarcoma and age-related degenerative diseases, such as osteoporosis and osteoarthritis. Understanding the physiological and pathological function of Notch signaling in skeletal tissues using animal models and human genetics will provide new insights into disease pathogenesis and offer novel approaches for the treatment of bone/cartilage diseases.

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“…Bone formation is mediated by osteoblasts recruited from bone mesenchymal cells (5), which can also differentiate into cells of other lineages, including myoblasts, chondrocytes, and adipocytes. The fate determination of bone marrow mesenchymal cells and their differentiation toward cells of the osteoblastic lineage is tightly controlled by several early regulators including: Wnt/β-catenin signaling, bone morphogenetic proteins (BMPs), hedgehog proteins, endocrine hormones, epigenetic regulators, and various growth factors.…”

Section: Introductionmentioning

confidence: 99%

Chordin-Like 1 Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells Through Enhancing BMP4-SMAD Pathway

Liu

Zheng

et al. 2019

Front. Endocrinol.

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Chordin-like 1 (CHRDL1) is a secreted glycoprotein with repeated cysteine-rich domains, which can bind to BMPs family ligands. Although it has been reported to play important roles in several systems, the exact roles of CHRDL1 on human bone mesenchymal stem cells (hBMSCs) osteogenesis remain to be explored. The present study aimed to investigate the roles of CHRDL1 on the osteogenic differentiation of hBMSCs and the underlying molecular mechanisms. We found that CHRDL1 was upregulated during hBMSCs osteogenesis, and rhBMP-4 administration could enhance CHRDL1 mRNA expression in a dose and time dependent manner. Knockdown of CHRDL1 did not affect hBMSCs proliferation, but inhibited the BMP-4-dependent osteogenic differentiation, showing decreased mRNA expression levels of osteogenic markers and reduced mineralization. On the contrary, overexpression of CHRDL1 enhanced BMP-4 induced osteogenic differentiation of hBMSCs. Moreover, in vivo experiments by transplanting CHRDL1 gene modified hBMSCs into nude mice defective femur models displayed higher new bone formation in CHRDL1 overexpression groups, but lower new bone formation in CHRDL1 knockdown groups, compared with control groups. In consistent with the bone formation rate, there were increased CHRDL1 protein expression in new bone formation regions of defective femur in CHRDL1 overexpression groups, while reduced CHRDL1 protein expression in CHRDL1 knockdown groups compared with control groups. These indicate that CHRDL1 can promote osteoblast differentiation in vivo . Furthermore, the mechanisms study showed that CHRDL1 improved BMP-4 induced phosphorylation of SMAD1/5/9 during osteogenic differentiation of hBMSCs. Besides, promotion of osteogenic differentiation and the activation of SMAD phosphorylation by CHRDL1 can be blocked by BMP receptor type I inhibitor LDN-193189. In conclusion, our results suggested that CHRDL1 can promote hBMSCs osteogenic differentiation through enhancing the activation of BMP-4-SMAD1/5/9 pathway.

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Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation

Cited by 85 publications

References 43 publications

The role of osteoblasts in energy homeostasis

The role of osteoblasts in energy homeostasis

Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis

Chordin-Like 1 Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells Through Enhancing BMP4-SMAD Pathway

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