The Experts below are selected from a list of 954 Experts worldwide ranked by ideXlab platform
Fusanori Nishimura - One of the best experts on this subject based on the ideXlab platform.
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sphingosine 1 phosphate S1PR2 mediated signaling triggers smad1 5 8 phosphorylation and thereby induces runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Fumi Takahashiyanaga, Aiko Takano, Hisashi Anan, Masato Hirata, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
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Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Aiko Takano, Hisashi Anan, Masato Hirata, Fumi Takahashi-yanaga, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
Etsuko Matsuzaki - One of the best experts on this subject based on the ideXlab platform.
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sphingosine 1 phosphate S1PR2 mediated signaling triggers smad1 5 8 phosphorylation and thereby induces runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Fumi Takahashiyanaga, Aiko Takano, Hisashi Anan, Masato Hirata, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
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Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Aiko Takano, Hisashi Anan, Masato Hirata, Fumi Takahashi-yanaga, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
Volker Brinkmann - One of the best experts on this subject based on the ideXlab platform.
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cardiac and vascular effects of fingolimod mechanistic basis and clinical implications
American Heart Journal, 2014Co-Authors: John Camm, Rajesh Bakshi, Volker BrinkmannAbstract:Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis; it reduces autoreactive lymphocytes' egress from lymphoid tissues by down-regulating S1PRs. Sphingosine-1-phosphate signaling is implicated in a range of physiologic functions, and S1PRs are expressed differentially in various tissues, including the cardiovascular system. Modulation of S1PRs on cardiac cells provides an explanation for the transient effects of fingolimod on heart rate and atrioventricular conduction at initiation of fingolimod therapy, and for the mild but more persistent effects on blood pressure observed in some patients on long-term treatment. This review describes the nontherapeutic actions of fingolimod in the context of sphingosine-1-phosphate signaling in the cardiovascular system, as well as providing a summary of the associated clinical implications useful to physicians considering initiation of fingolimod therapy in patients. A transient reduction in heart rate (mean decrease of 8 beats per minute) and, less commonly, a temporary delay in atrioventricular conduction observed in some patients when initiating fingolimod therapy are both due to activation of S1PR subtype 1 on cardiac myocytes. These effects are a reflection of fingolimod first acting as a full S1PR agonist and thereafter functioning as an S1PR antagonist after down-regulation of S1PR subtype 1 at the cell surface. For most individuals, first-dose effects of fingolimod are asymptomatic, but all patients need to be monitored for at least 6 hours after the first dose, in accordance with the label recommendations.
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sphingosine 1 phosphate s1p physiology and the effects of s1p receptor modulation
Neurology, 2011Co-Authors: Volker BrinkmannAbstract:Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P 1–5 , have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P 1 prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P 1 -directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P 1 in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.
Katsumasa Higashi - One of the best experts on this subject based on the ideXlab platform.
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sphingosine 1 phosphate S1PR2 mediated signaling triggers smad1 5 8 phosphorylation and thereby induces runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Fumi Takahashiyanaga, Aiko Takano, Hisashi Anan, Masato Hirata, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
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Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts
Bone, 2016Co-Authors: Katsumasa Higashi, Etsuko Matsuzaki, Yoko Hashimoto, Aiko Takano, Hisashi Anan, Masato Hirata, Fumi Takahashi-yanaga, Fusanori NishimuraAbstract:Abstract Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo . These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
Guanghui Yi - One of the best experts on this subject based on the ideXlab platform.
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apoa i sr bi modulates s1p S1PR2 mediated inflammation through the pi3k akt signaling pathway in huvecs
Journal of Physiology and Biochemistry, 2017Co-Authors: Yanju Lu, Zhongcheng Mo, Zhenli Tang, Yue Jiang, Xiaoshan Peng, Li Li, Qinghai Zhang, Guanghui YiAbstract:Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.
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ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.
Journal of Physiology and Biochemistry, 2017Co-Authors: Yanju Lu, Zhongcheng Mo, Zhenli Tang, Yue Jiang, Xiaoshan Peng, Li Li, Qinghai Zhang, Guanghui YiAbstract:Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.
