title: Retinoic acid remodels extracellular matrix (ECM) of cultured human fetal palate mesenchymal cells (hFPMCs) through down-regulation of TGF-β/Smad signaling.
abstract: The regulation of extracellular matrix (ECM) by retinoic acid (RA) is interesting in light of the fact that the ECM plays an essential role in morphogenesis and palatal shelf elevation. In the current study, we explored the effect of RA overexposure on ECM and the probable mechanisms in cultured human fetal palate mesenchymal cells (hFPMCs). RA dose-dependently inhibited cell proliferation and mRNA and protein levels of ECM components fibronectin, tenascin C and fibrillin-2. Zymography revealed that MMP-2 activity was suppressed by RA. Further analysis revealed that mRNA levels of MMP2 and TIMP2 were decreased, while the MMP2/TIMP2 mRNA ratio was increased, which might facilitate the ECM degradation. Because of the pivotal role of TGF-β/Smad pathway in palatogenesis we therefore checked the effect of RA on TGF-β/Smad signaling. The results indicated RA treatment increased Smad7 expression and decreased the levels of TGF-β1, TGF-β3, TGF-β type II receptor (TβRII) and phosphorylated Smad2 and Smad3. Activation of the Smad pathways by either exogenous TGF-β3 or recombinant adenoviruses for Smad3 attenuated RA-induced inhibition of cell proliferation and ECM components and rescued the RA-altered MMP2/TIMP2 mRNA ratio. In conclusion, these findings suggested that RA overexposure inhibited cell proliferation and disrupted the ECM network through down-regulation of TGF-β/Smad pathway.
authors.affiliation: Public Health College, Zhengzhou University, 450001, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Public Health College, Zhengzhou University, 450001, China.
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Yin
authors.affiliation: The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Public Health College, Zhengzhou University, 450001, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Public Health College, Zhengzhou University, 450001, China.
authors.forename: Xiaozhuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Public Health College, Zhengzhou University, 450001, China.
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Public Health College, Zhengzhou University, 450001, China; Henan Agriculture University, 450002, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Public Health College, Zhengzhou University, 450001, China. Electronic address: zly@zzu.edu.cn.
authors.forename: Zengli
authors.initials: Z
authors.lastname: Yu
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010159:Palate / Q000166:cytology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; C508960:TGFB1 protein, human; C509044:TGFB3 protein, human; C560823:TIMP2 protein, human; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D019716:Tissue Inhibitor of Metalloproteinase-2; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Extracellular matrix (ECM); Human fetal palate mesenchymal cells (hFPMCs); Retinoic acid; TGF-β/Smad signaling