Department of Pulp Biology and Endodontics, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
Sci Rep. 2018 Jun 15;8(1):9224. doi: 10.1038/s41598-018-27461-7.
This study examined the effects and mechanisms of strontium ranelate (SrRn)-a drug used to treat osteoporosis-on the proliferation and differentiation/mineralization of cloned dental pulp-like cells (mouse dental papillae cells; MDPs). It also determined whether topical application of SrRn to exposed dental pulp tissue promotes the formation of mineralized tissue in vivo. The MDPs were cultured with or without SrRn, and cell proliferation, odonto-/osteoblastic gene expression, mineralized nodule formation, and Akt phosphorylation were evaluated. The formation of mineralized tissue in SrRn-treated pulp tissue in rat upper first molars was evaluated histologically. The SrRn up-regulated cell proliferation and expression of Alp (alkaline phosphatase), Bsp (bone sialoprotein), Dmp (dentin matrix acidic phosphoprotein)-1, Dspp (dentin sialophosphoprotein), and Oc (osteocalcin) in a dose-dependent manner. Mineralized nodule formation was also enhanced by SrRn. NPS-2143, a calcium-sensing receptor (CaSR) antagonist, and siRNA against the CaSR gene blocked SrRn-induced proliferation, odonto-/osteoblastic gene expression, and mineralized nodule formation. SrRn induced Akt phosphorylation, and this was blocked by NPS-2143. Topical application of SrRn to exposed rat molar pulps induced the formation of osteodentin-like mineralized tissue. Our study revealed for the first time that SrRn promotes proliferation and odonto-/osteogenic differentiation/mineralization of MDPs via PI3K/Akt signaling activated by CaSR in vitro; mineralized tissue forms from the dental pulp in vivo.
本研究探讨了雷奈酸锶（SrRn）——一种用于治疗骨质疏松症的药物——对克隆牙髓样细胞（小鼠牙乳头细胞；MDPs）增殖和分化/矿化的影响及其机制。还确定了 SrRn 局部应用于暴露的牙髓组织是否能促进体内矿化组织的形成。在有或没有 SrRn 的情况下培养 MDPs，并评估细胞增殖、牙/成骨基因表达、矿化结节形成和 Akt 磷酸化。通过组织学评估 SrRn 处理的大鼠上颌第一磨牙牙髓组织中矿化组织的形成。SrRn 以剂量依赖性方式上调 Alp（碱性磷酸酶）、Bsp（骨涎蛋白）、Dmp（牙基质酸性磷酸蛋白-1）、Dspp（牙涎磷蛋白）和 Oc（骨钙素）的细胞增殖和表达。矿化结节的形成也被 SrRn 增强。钙敏感受体（CaSR）拮抗剂 NPS-2143 和针对 CaSR 基因的 siRNA 阻断 SrRn 诱导的增殖、牙/成骨基因表达和矿化结节形成。SrRn 诱导 Akt 磷酸化，而 NPS-2143 则阻断了这一作用。SrRn 局部应用于暴露的大鼠磨牙牙髓可诱导形成类骨/牙本质矿化组织。本研究首次揭示，SrRn 通过 CaSR 激活的 PI3K/Akt 信号通路促进 MDPs 的增殖和牙/成骨分化/矿化；体内来自牙髓的矿化组织形成。
