Suberoylanilide Hydroxamic Acid Enhances Odontoblast Differentiation

Abstract

Previous studies have shown that histone deacetylase (HDAC) inhibitors stimulate osteoblast differentiation in vitro and bone formation in vivo. However, the effects of HDAC inhibitors on odontoblasts have not been elucidated. Therefore, in this study, we examined the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on odontoblast differentiation using an MDPC23 odontoblast-like cell line. SAHA significantly enhanced matrix mineralization and the expression levels of odontoblast marker genes. SAHA increased the expression levels of nuclear factor I/C (Nfic) and dentin sialophosphoprotein (Dspp). Nfic bound directly to the Dspp promoter and stimulated Dspp transcription. SAHA increased both basal and Nfic-induced Dspp promoter activity. SAHA-induced Dspp promoter activity disappeared when mutations were introduced within the Nfic binding element of the Dspp promoter. Nfic knockdown by siRNA blocked SAHA stimulation of Dspp expression. These results indicate that SAHA enhances odontoblast differentiation and that SAHA increases Dspp expression, at least in part, by increasing the expression level of Nfic.

Epigenetic modulation of dental pulp stem cells: implications for regenerative endodontics

“…Accompanying significant increased transcription of the mineralization-associated genes, transforming growth factor beta-1 (TGF-b1), bone morphogenetic protein-4 (BMP-4) and the dentinogenic transcript DMP-1 were noted, leading to the conclusion that HDACi can epigenetically modulate the cell enabling acceleration of mineralization and odontoblast-like cell differentiation. These results were further corroborated with the same cell line using a different HDACi (SAHA), which also enhanced matrix mineralization and the expression levels of the odontoblast differentiation markers nuclear factor I/C (Nfic) and DSPP as well as increasing the acetylation of the core histone H3 (Kwon et al 2012). Furthermore, it was demonstrated that Nfic bound directly to the DSPP promoter and stimulated DSPP transcription suggesting a possible mechanism by which SAHA promoted odontogenic events.…”

“…These results were further corroborated with the same cell line using a different HDACi (SAHA), which also enhanced matrix mineralization and the expression levels of the odontoblast differentiation markers nuclear factor I/C (Nfic) and DSPP as well as increasing the acetylation of the core histone H3 (Kwon et al . ). Furthermore, it was demonstrated that Nfic bound directly to the DSPP promoter and stimulated DSPP transcription suggesting a possible mechanism by which SAHA promoted odontogenic events.…”

“…Several recent endodontic-related studies using dental papilla derived pulp cell lines (Duncan et al 2012, Kwon et al 2012, primary rat DPCs (Duncan et al 2013) and human DPSCs (Jin et al 2013, Paino et al 2014 have demonstrated that HDACis stimulate odontoblast-like cell differentiation with an associated increase in matrix mineral deposition in vitro (Table 2). Duncan et al (2012) in the first of these studies supplemented TSA and VPA, at a range of concentrations to a dental papilla derived cell line and analysed a range of downstream markers including proliferation, viability and mineralization.…”

CPNE7, a preameloblast-derived factor, regulates odontoblastic differentiation of mesenchymal stem cells

“…Next, we investigated whether the Cpne7-Nucleolin complex binds specifically to the Dspp promoter. A positive control was designed using the well-characterized nuclear factor IeC antibody on DSPP promoter [28]. Chromatin immunoprecipitation (ChIP) assay revealed that Nucleolin bound to the Dspp promoter, whereas negative control (pre-immune serum) or Nucleolin siRNA did not precipitate the Dspp promoter fragment (Fig.…”

Nuclear Factor I-C (NFIC) Regulates Dentin Sialophosphoprotein (DSPP) and E-cadherin via Control of Krüppel-like Factor 4 (KLF4) During Dentinogenesis

“…Disruption of the Nfic gene in mice leads to abnormal tooth roots that are predominantly caused by abnormal odontoblast differentiation and dentin formation during root formation (5-7). Previously, we suggested that Nfic transcriptionally activates DSPP expression (8).…”