title: P38/JNK signaling pathway mediates the fluoride-induced down-regulation of Fam83h.
abstract: OBJECTIVE
  The similar clinical and pathological feature in fluorosis and amelogenesis imperfect with FAM83H mutations imply that excess fluoride could have effects on the expression of FAM83H and could elaborate this process by some signal pathways regulation. The present study aims to investigate the effects of fluoride on Fam83h expression and try to explore the molecular signaling regulation between them as well as the association of high concentration fluoride with mineralization in ameloblast lineage cells.
  
  
  METHODS
  Protein expression and signaling pathways of mouse ameloblast-like LS8 cells, exposed to fluoride or MAPK inhibitors, were compared to control cells without exposure. Fam83h, proteins of MAPK signal pathways (ERK, P38 and JNK) were examined by Quantitative real-time PCR and/or Western-blot. ALP activity and ALP staining were used to detect the mineralization in the cells with exposure during 7-day mineralization inducing differentiation.
  
  
  RESULTS
  The results showed that Fam83h protein level in LS8 cells decreased in the presence of fluoride and MAPK inhibitors. Down-regulation of Fam83h by fluoride was related to suppression of JNK and P38 phosphorylation, and the descending degree of P38 was more obvious. Fluoride and MAPK inhibitors treatment significantly decreased the mineralization level in LS8 cells.
  
  
  CONCLUSIONS
  The findings suggest that JNK and P38 could be key regulatory element for Fam83h expression, and that LS8 cells can respond to fluoride by down-regulating Fam83h expression through the regulation of JNK and p38 signaling pathways.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China; The First Affiliated Hospital of Henan University, 357 Ximen Road, Kaifeng 471000, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jia
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China.
authors.forename: Changning
authors.initials: C
authors.lastname: Wang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China. Electronic address: sningya@whu.edu.cn.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Song
mesh_terms: D000565:Ameloblasts / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008903:Minerals / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012969:Sodium Fluoride / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C587940:FAM83h protein, mouse; D008903:Minerals; D011506:Proteins; D012969:Sodium Fluoride; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Amelogenesis imperfect; Fam83h; Fluorosis; Mineralization