IL-1β-induced, matrix metalloproteinase-3-regulated proliferation of embryonic stem cell-derived odontoblastic cells is mediated by the Wnt5 signaling pathway.
We previously established a method for differentiating induced pluripotent stem cells and embryonic stem (ES) cells into α2 integrin-positive odontoblast-like cells. We also reported that interleukin (IL)-1β induces matrix metalloproteinase (MMP)-3-regulated cell proliferation and suppresses apoptosis in these cells, suggesting that MMP-3 plays a potentially unique physiological role in the regeneration of odontoblast-like cells. Here, we examined whether up-regulation of MMP-3 activity by IL-1β was mediated by Wnt signaling and led to increased proliferation of odontoblast-like cells. IL-1β increased mRNA and protein levels of Wnt5a, Wnt5b and the Wnt receptor Lrp5. Exogenous Wnt5a and Wnt5b were found to increase MMP-3 mRNA, protein and activity, and interestingly the rate of proliferation in these cells. Treatment with siRNAs against Wnt5a, Wnt5b and Lrp5 suppressed the IL-1β-induced increase in MMP-3 expression and suppressed cell proliferation, an effect rescued by application of exogenous Wnt5. These results demonstrate the sequential involvement of Wnt5, Lrp5 and MMP-3 in effecting IL-1β-induced proliferation of ES cell-derived odontoblast-like cells.
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Nobuaki
N
Ozeki
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Naoko
N
Hase
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Taiki
T
Hiyama
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Hideyuki
H
Yamaguchi
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Rie
R
Kawai
Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
Ayami
A
Kondo
Department of Endodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi 464-8651, Japan.
Kazuhiko
K
Nakata
Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan. Electronic address: makio@dpc.agu.ac.jp.
Makio
M
Mogi
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009804:Odontoblasts / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D012333:RNA, Messenger; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C468567:Wnt5b protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse
Cell proliferation; Interleukin-1β; Lrp5; Matrix metalloproteinase; Odontoblast; Wnt5