Sphingosine-1-phosphate promotes the nuclear translocation of β-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines

Matsuzaki, Etsuko; Shunji, Hiratsuka; Hamachi, Toshihiro; Takahashi-Yanaga, Fumi; Hashimoto, Yusuke; Higashi, Katsumasa; Kobayashi, Mari; Hirofuji, Takao; Hirata, Masato; Maeda, Katsumasa

doi:10.1016/j.bone.2013.04.008

Cited by 58 publications

(81 citation statements)

References 44 publications

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“…The increased S1P and PAF levels in the KO mice explain not only the tumorigenesis but also the increased expression and nuclear translocation of b-catenin, a key transcriptional factor for cell survival (38), because both S1P and PAF are known to stimulate synthesis and translocation of b-catenin in cancer cells, including intestinal epithelial cells (39)(40)(41). Overexpression of PAF acetylhydrolase reduces the amount of nuclear b-catenin and induces a shift of the protein from the nucleus to the cytoplasm (42).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Chen

Zhang

et al. 2015

Molecular Cancer Therapeutics

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Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. b-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of b-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels.

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Section: Discussionmentioning

confidence: 99%

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Chen

Zhang

et al. 2015

Molecular Cancer Therapeutics

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“…S1P regulates many cellular responses such as migration, growth, and differentiation [15,[17][18][19]. The current authors [20] and others [21] have previously reported that S1P induces osteogenic differentiation of osteoblast-like cells.…”

Section: Introductionmentioning

confidence: 90%

Sphingosine-1-phosphate inhibits differentiation of C3H10T1/2 cells into adipocyte

et al. 2014

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Mesenchymal stem cells (MSCs) can differentiate into a number of cell types, including adipocytes and osteoblasts. MSC differentiation into adipocytes inhibits osteogenic differentiation and vice versa. Therefore, understanding the mechanisms of MSC differentiation at the signaling level can lead to the development of novel therapeutic strategies toward tissue regeneration. Sphingosine-1-phosphate (S1P) is a signaling molecule that regulates many cellular responses, including cellular differentiation. However, the effects of S1P on MSC differentiation are largely unknown. The purpose of study was to investigate whether S1P drives MSCs toward either adipogenic or osteogenic differentiation, and if so, to clarify the underlying signaling mechanisms for such differentiation. We found that S1P inhibited adipogenic differentiation of C3H10T1/2 multipotent stem cells, while promoting their osteogenic differentiation. During adipogenic differentiation, S1P suppressed the cAMP accumulation in a Gi-protein-dependent manner. The Gi-dependent S1P signaling suppressed C/EBPβ expression, which is essential for adipogenic differentiation. Furthermore, S1P did not affect cAMP-independent adipogenic differentiation. These findings suggest that S1P suppresses cAMP accumulation, leading to inhibition of C/EBPβ expression, thereby resulting in decreased adipogenic differentiation of C3H10T1/2 cells. Thus, our findings provide novel molecular mechanisms as regards how S1P inhibits adipogenic differentiation of C3H10T1/2 cells, indicating a potential beneficial role for regeneration and repair of tissues.

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“…In a different study, the role of TGF-beta1 on osteoclast-mediated support of mineralization was investigated and revealed that S1P production was, however, not induced in osteoclasts upon TGF-beta1 stimulation [83]. Up-regulation of OPG and osteoblast differentiation markers upon S1P stimulation was another finding which may lead to the inhibition of osteoclast differentiation and promotion of bone formation [84]. Thereby S1P may coordinate the balance between bone formation and bone resorption.…”

Section: Function Of S1p In Bloodmentioning

confidence: 99%

Sphingosine 1-Phosphate in Blood: Function, Metabolism, and Fate

Thuy

Reimann

Hemdan

et al. 2014

Cell Physiol Biochem

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Sphingosine 1-phosphate (S1P) is a lipid metabolite and a ligand of five G protein-coupled cell surface receptors S1PR1 to S1PR5. These receptors are expressed on various cells and cell types of the immune, cardiovascular, respiratory, hepatic, reproductive, and neurologic systems, and S1P has an impact on many different pathophysiological conditions including autoimmune, cardiovascular, and neurodegenerative diseases, cancer, deafness, osteogenesis, and reproduction. While these diverse signalling properties of S1P have been extensively reviewed, the particular role of S1P in blood is still a matter of debate. Blood contains the highest S1P concentration of all body compartments, and several questions are still not sufficiently answered: Where does it come from and how is it metabolized? Why is the concentration of S1P in blood so high? Are minor changes of the high blood S1P concentrations physiologically relevant? Do blood cells and vascular endothelial cells that are constantly exposed to high blood S1P levels still respond to S1P via S1P receptors? Recent data reveal new insights into the functional role and the metabolic fate of blood-borne S1P. This review aims to summarize our current knowledge regarding the source, secretion, transportation, function, metabolism, and fate of S1P in blood.

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Sphingosine-1-phosphate promotes the nuclear translocation of β-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines

Cited by 58 publications

References 44 publications

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Sphingosine-1-phosphate inhibits differentiation of C3H10T1/2 cells into adipocyte

Sphingosine 1-Phosphate in Blood: Function, Metabolism, and Fate

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