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    • s6 kinase During the tooth morphogenesis growth factors and

    2018-11-12

    During the tooth morphogenesis, growth factors and other paracrine signal molecules mediate the interactions both between and within the epithelial and mesenchymal tissues, such as the fibroblast growth factors (FGFs), transforming growth factors (TGFs), bone morphogenetic proteins (BMPs), and insulin-like growth factors (IGFs) (Caton and Tucker, 2009; Torres et al., 2006, 2008). FGF signaling pathways are important to the s6 kinase of mammalian dentition by giving rise to new cusps and crests (Charles et al., 2009). Among BMP family members, BMP2 has been extensively studied for its biological functions during root development, and it can promote dental pulp stem cell commitment to the odontoblast lineage (Yang et al., 2009). IGF-1 and IGF-2 play an important role in the regulation of tooth growth and differentiation. Tooth explants treated with IGF-1 show an increase in both dentin and enamel matrix, while IGF-2 appears to preferentially affect the enamel deposition (Caton et al., 2005). Following the odontoblastic differentiation, IGF-1 level is significantly up-regulated (Liu et al., 2009). There is a statistically significant difference of IGF-1 expression between immature and mature dental pulps (Caviedes-Bucheli et al., 2004, 2007), and exogenous IGF-1 can elongate the molar roots (Fujiwara et al., 2005). However, little knowledge is available about its effect on the differentiation of SCAPs. In the present study, we hypothesize that IGF-1 plays an important role in the proliferation and differentiation of SCAPs. For this purpose, SCAPs were isolated from immature human third molar apex and treated with exogenous IGF-1. The effects of IGF-1 on SCAPs were subsequently evaluated both in vitro and in vivo. Our experimental data showed that the osteogenic differentiation and osteogenesis of SCAPs were enhanced by IGF-1, while their odontogenic differentiation and dentinogenesis were weakened, indicating that these IGF-1 treated SCAPs can be used as a potential candidate for bone tissue engineering.
    Results
    Discussion There is a growing evidence that IGFs play an important role in the development of oro-dento-facial tissues and organs (Caton et al., 2005; Werner and Katz, 2004; Yamamoto et al., 2006), in which IGF-1 is involved in various processes including tooth development, growth, periodontal ligament homeostasis and different pathological circumstances (Caton et al., 2005; Fujiwara et al., 2005; Kheralla et al., 2010; Rath-Deschner et al., 2009). Diverse studies have revealed that IGF-1 can affect the odontogenic differentiation and dentin regeneration (Caton et al., 2007; Young, 1995). Moreover, IGF-1 can induce dental papilla cells to secrete the bone-like extracellular matrix (Caton et al., 2007). Previous studies have proved that SCAPs have a potent capacity to differentiate along the odontoblast lineages and perform the typical dentinogenesis (Abe et al., 2008; Lei et al., 2011; Sonoyama et al., 2006; Sonoyama et al., 2008). Therefore, it is reasonable that IGF-1 may have some distinguishable effects on the differentiation of SCAPs. In this study, exogenous IGF-1 can stimulate the proliferation and modify the ultrastructural morphology of SCAPs in vitro. Besides, IGF-1 can up-regulate the ALP activity, the mineralization capacity, and expression of several osteoblast-related markers (ALP, RUNX2, OSX, OCN) in SCAPs. As a characteristic marker of osteoblast phenotype, ALP is an important marker during the early stage of osteogenic differentiation (Hanai et al., 2006; Hong et al., 2010; Park et al., 2009). The transcription factors RUNX2 and OSX are also necessary for osteogenic differentiation (Baek et al., 2009; Kaback et al., 2008; Komori, 2006). Disruption of RUNX2 and OSX can result in a complete lack of bone formation and tooth germ abnormality (Kobayashi et al., 2006). Moreover, RUNX2 can inhibit the terminal differentiation of odontoblasts, induce the transdifferentiation of odontoblasts into osteoblast lineages and form a bone structure (Miyazaki et al., 2008). OCN is thought to play an important role in the osteogenic differentiation and mineralization at the late stages of bone formation. DSPP gene and DSP protein are the putative differentiation markers of odontoblast lineages. They are involved in the nucleation and control of the hydroxyapatite mineral phase during dentin calcification (Lee et al., 2009; McKnight et al., 2008). Thus, the up-regulation of osteoblast markers (i.e., RUNX2, OSX, OCN, and ALP) and down-regulation of odontoblast markers (i.e., DSPP and DSP) in IGF-1 treated group suggests that IGF-1 can enhance the osteogenic differentiation but weaken the odontogenic differentiation of SCAPs. Moreover, the expression level of DSPP is quite low in both treated and untreated SCAPs. The plausible explanation for this phenomenon is that SCAPs from the developing dental tissues are more primitive and they cannot achieve full odontoblastic differentiation under in vitro culture conditions due to the loss of suitable microenvironment (Sonoyama et al., 2008).