title: Activation of canonical Wnt/β-catenin signaling inhibits H2O2-induced decreases in proliferation and differentiation of human periodontal ligament fibroblasts.
abstract: Human periodontal ligament fibroblasts (hPLFs) are exposed to oxidative stress during periodontal inflammation and dental treatments. It is hypothesized that hydrogen peroxide (H2O2)-mediated oxidative stress decreases survival and osteogenic differentiation of hPLFs, whereas these decreases are prevented by activation of the Wnt pathway. However, there has been a lack of reports that define the exact roles of canonical Wnt/β-catenin signaling in H2O2-exposed hPLFs. Treatment with H2O2 reduced viability and proliferation in hPLFs in a dose- and time-dependent manner and led to mitochondria-mediated apoptosis. Pretreatment with lithium chloride (LiCl) or Wnt1 inhibited the oxidative damage that occurred in H2O2-exposed hPLFs. However, knockout of β-catenin or treatment with DKK1 facilitated the H2O2-induced decreases in viability, mitochondrial membrane potential, and Bcl-2 induction. Osteoblastic differentiation of hPLFs was also inhibited by combined treatment with 100 μM H2O2, as evidenced by the decreases in alkaline phosphatase (ALP) activity and mineralization. H2O2-mediated inhibition of osteoblast differentiation in hPLFs was significantly attenuated in the presence of 500 ng/ml Wnt1 or 20 mM LiCl. In particular, H2O2 stimulated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) at protein and mRNA levels in hPLFs, whereas the induction was almost completely suppressed in the presence of Wnt1 or LiCl. Furthermore, siRNA-mediated silencing of Nrf2 blocked H2O2-induced decreases in ALP activity and mineralization of hPLFs with the concomitant restoration of runt-related transcription factor 2 and osteocalcin mRNA expression and ALP activity. Collectively, these results suggest that activation of the Wnt/β-catenin pathway improves proliferation and mineralization in H2O2-exposed hPLFs by downregulating Nrf2.
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kook
authors.affiliation: Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Daewoo
authors.initials: D
authors.lastname: Lee
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Eui-Sic
authors.initials: ES
authors.lastname: Cho
authors.affiliation: Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul, 130-701, South Korea.
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Heo
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Sher Bahadur
authors.initials: SB
authors.lastname: Poudel
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Yu-Hyeon
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Hyeok
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Jong-Ghee
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea. leejc88@jbnu.ac.kr.|Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea. leejc88@jbnu.ac.kr.
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D006861:Hydrogen Peroxide; D000469:Alkaline Phosphatase
keywords: Differentiation; Human periodontal ligament fibroblasts; Hydrogen peroxide; Nrf2; Wnt pathway