Hesperetin alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of periodontal ligament stem cells

Hesperetin (3',5,7-trihydroxy-4-methoxyflavanone) is a metabolite of hesperidin (hesperetin-7-O-rutinoside), which belongs to the flavanone subgroup and is found mainly in citrus fruits. Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro mode...

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Veröffentlicht in:PloS one 2013-06, Vol.8 (6), p.e67504
Hauptverfasser: Kim, So Yeon, Lee, Jin-Yong, Park, Yong-Duk, Kang, Kyung Lhi, Lee, Jeong-Chae, Heo, Jung Sun
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Lee, Jeong-Chae
Heo, Jung Sun
description Hesperetin (3',5,7-trihydroxy-4-methoxyflavanone) is a metabolite of hesperidin (hesperetin-7-O-rutinoside), which belongs to the flavanone subgroup and is found mainly in citrus fruits. Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro models. However, how hesperetin effects osteogenic differentiation is not fully understood. In this study, we investigated the capacity of hesperetin to stimulate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to relieve the anti-osteogenic effect of high glucose. Osteogenesis of PDLSCs was assessed by measurement of alkaline phosphatase (ALP) activity, and evaluation of the mRNA expression of ALP, runt-related gene 2 (Runx2), osterix (OSX), and FRA1 as osteogenic transcription factors, as well as assessment of protein expression of osteopontin (OPN) and collagen type IA (COLIA). When PDLSCs were exposed to a high concentration (30 mM) of glucose, osteogenic activity decreased compared to control cells. Hesperetin significantly increased ALP activity at doses of 1, 10, and 100 µM. Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. Collectively, our results suggest that hesperetin alleviates the high glucose-mediated suppression of osteogenic differentiation in PDLSCs by regulating ROS levels and the PI3K/Akt and β-catenin signaling pathways.
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Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro models. However, how hesperetin effects osteogenic differentiation is not fully understood. In this study, we investigated the capacity of hesperetin to stimulate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to relieve the anti-osteogenic effect of high glucose. Osteogenesis of PDLSCs was assessed by measurement of alkaline phosphatase (ALP) activity, and evaluation of the mRNA expression of ALP, runt-related gene 2 (Runx2), osterix (OSX), and FRA1 as osteogenic transcription factors, as well as assessment of protein expression of osteopontin (OPN) and collagen type IA (COLIA). When PDLSCs were exposed to a high concentration (30 mM) of glucose, osteogenic activity decreased compared to control cells. Hesperetin significantly increased ALP activity at doses of 1, 10, and 100 µM. Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. Collectively, our results suggest that hesperetin alleviates the high glucose-mediated suppression of osteogenic differentiation in PDLSCs by regulating ROS levels and the PI3K/Akt and β-catenin signaling pathways.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0067504</identifier><identifier>PMID: 23840726</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Alkaline phosphatase ; Alkaline Phosphatase - genetics ; Alkaline Phosphatase - metabolism ; beta Catenin - genetics ; beta Catenin - metabolism ; Biocompatibility ; Biology ; Biomedical engineering ; Biomedical materials ; Blockage ; Cbfa-1 protein ; Cell Differentiation - drug effects ; Cell Differentiation - genetics ; Cells, Cultured ; Citrus fruits ; Collagen ; Dentistry ; Diabetes ; Differentiation ; Flavonoids ; Fra1 protein ; Fruits ; Gene expression ; Gene Expression - drug effects ; Gene Expression - genetics ; Glucose ; Glucose - metabolism ; Hesperetin ; Hesperidin ; Hesperidin - pharmacology ; Humans ; Kinases ; Ligaments ; Metabolites ; Osteoblastogenesis ; Osteoblasts ; Osteoblasts - drug effects ; Osteoblasts - metabolism ; Osteogenesis ; Osteogenesis - drug effects ; Osteogenesis - genetics ; Osteopontin ; Oxidative stress ; Oxygen ; Pathways ; Periodontal ligament ; Periodontal Ligament - drug effects ; Periodontal Ligament - metabolism ; Phosphatase ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Pretreatment ; Proteins ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Signaling ; Stem cells ; Stem Cells - drug effects ; Stem Cells - metabolism ; Transcription factors ; Transcription Factors - genetics ; Transcription Factors - metabolism ; β-Catenin</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e67504</ispartof><rights>2013 Kim et al. 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Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. 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drug effects</subject><subject>Gene Expression - genetics</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Hesperetin</subject><subject>Hesperidin</subject><subject>Hesperidin - pharmacology</subject><subject>Humans</subject><subject>Kinases</subject><subject>Ligaments</subject><subject>Metabolites</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Osteoblasts - drug effects</subject><subject>Osteoblasts - metabolism</subject><subject>Osteogenesis</subject><subject>Osteogenesis - drug effects</subject><subject>Osteogenesis - genetics</subject><subject>Osteopontin</subject><subject>Oxidative stress</subject><subject>Oxygen</subject><subject>Pathways</subject><subject>Periodontal ligament</subject><subject>Periodontal Ligament - drug effects</subject><subject>Periodontal Ligament - metabolism</subject><subject>Phosphatase</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - 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genetics</topic><topic>Alkaline Phosphatase - metabolism</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Biocompatibility</topic><topic>Biology</topic><topic>Biomedical engineering</topic><topic>Biomedical materials</topic><topic>Blockage</topic><topic>Cbfa-1 protein</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - genetics</topic><topic>Cells, Cultured</topic><topic>Citrus fruits</topic><topic>Collagen</topic><topic>Dentistry</topic><topic>Diabetes</topic><topic>Differentiation</topic><topic>Flavonoids</topic><topic>Fra1 protein</topic><topic>Fruits</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression - genetics</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Hesperetin</topic><topic>Hesperidin</topic><topic>Hesperidin - pharmacology</topic><topic>Humans</topic><topic>Kinases</topic><topic>Ligaments</topic><topic>Metabolites</topic><topic>Osteoblastogenesis</topic><topic>Osteoblasts</topic><topic>Osteoblasts - 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Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro models. However, how hesperetin effects osteogenic differentiation is not fully understood. In this study, we investigated the capacity of hesperetin to stimulate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to relieve the anti-osteogenic effect of high glucose. Osteogenesis of PDLSCs was assessed by measurement of alkaline phosphatase (ALP) activity, and evaluation of the mRNA expression of ALP, runt-related gene 2 (Runx2), osterix (OSX), and FRA1 as osteogenic transcription factors, as well as assessment of protein expression of osteopontin (OPN) and collagen type IA (COLIA). When PDLSCs were exposed to a high concentration (30 mM) of glucose, osteogenic activity decreased compared to control cells. Hesperetin significantly increased ALP activity at doses of 1, 10, and 100 µM. Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. Collectively, our results suggest that hesperetin alleviates the high glucose-mediated suppression of osteogenic differentiation in PDLSCs by regulating ROS levels and the PI3K/Akt and β-catenin signaling pathways.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23840726</pmid><doi>10.1371/journal.pone.0067504</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2013-06, Vol.8 (6), p.e67504
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1372350740
source Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry
subjects 1-Phosphatidylinositol 3-kinase
AKT protein
Alkaline phosphatase
Alkaline Phosphatase - genetics
Alkaline Phosphatase - metabolism
beta Catenin - genetics
beta Catenin - metabolism
Biocompatibility
Biology
Biomedical engineering
Biomedical materials
Blockage
Cbfa-1 protein
Cell Differentiation - drug effects
Cell Differentiation - genetics
Cells, Cultured
Citrus fruits
Collagen
Dentistry
Diabetes
Differentiation
Flavonoids
Fra1 protein
Fruits
Gene expression
Gene Expression - drug effects
Gene Expression - genetics
Glucose
Glucose - metabolism
Hesperetin
Hesperidin
Hesperidin - pharmacology
Humans
Kinases
Ligaments
Metabolites
Osteoblastogenesis
Osteoblasts
Osteoblasts - drug effects
Osteoblasts - metabolism
Osteogenesis
Osteogenesis - drug effects
Osteogenesis - genetics
Osteopontin
Oxidative stress
Oxygen
Pathways
Periodontal ligament
Periodontal Ligament - drug effects
Periodontal Ligament - metabolism
Phosphatase
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Pretreatment
Proteins
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Reactive oxygen species
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Signal Transduction - genetics
Signaling
Stem cells
Stem Cells - drug effects
Stem Cells - metabolism
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
β-Catenin
title Hesperetin alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of periodontal ligament stem cells
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