FAM20C phosphorylates secretory proteins at S-x-E/pS motifs, and previous studies of Fam20C-dificient mice revealed that FAM20C played essential roles in bone and tooth formation. Inactivation of FAM20C in mice led to hypophosphatemia that masks direct effect of FAM20C in these tissues, and consequently the direct role of FAM20C remains unknown. Our previous study reported that osteoblast/odontoblast-specific Fam20C transgenic (Fam20C-Tg) mice had normal serum phosphate levels and that osteoblastic FAM20C-mediated phosphorylation regulated bone formation and resorption. Here, we investigated the direct role of FAM20C in dentin using Fam20C-Tg mice. The tooth of Fam20C-Tg mice contained numerous highly phosphorylated proteins, including SIBLINGs, compared to that of wild-type mice. In Fam20C-Tg mice, coronal dentin volume decreased and mineral density unchanged at early age, while the volume unchanged and the mineral density elevated at maturity. In these mice, radicular dentin volume and mineral density decreased at all ages, and histologically, the radicular dentin had wider predentin and abnormal apical-side dentin with embedded cells and argyrophilic canaliculi. Immunohistochemical analyses revealed that abnormal apical-side dentin had bone and dentin matrix properties accompanied with osteoblast-lineage cells. Further, in Fam20C-Tg mice, DSPP content which is important for dentin formation, was reduced in dentin, especially radicular dentin, which might lead to defects mainly in radicular dentin. Renal subcapsular transplantations of tooth germ revealed that newly formed radicular dentin replicated apical abnormal dentin of Fam20C-Tg mice, corroborating that FAM20C overexpression indeed caused the abnormal dentin. Our findings indicate that odontoblastic FAM20C-mediated phosphorylation in the tooth regulates dentin formation and odontoblast differentiation.

FAM20C 在 SxE/pS 基序上磷酸化分泌蛋白，之前对 Fam20C 缺陷小鼠的研究表明，FAM20C 在骨骼和牙齿形成中发挥着重要作用。小鼠中 FAM20C 失活导致低磷血症，从而掩盖了 FAM20C 在这些组织中的直接作用，因此 FAM20C 的直接作用仍然未知。我们之前的研究报道，成骨细胞/成牙本质细胞特异性Fam20C转基因 (Fam20C-Tg) 小鼠具有正常的血清磷酸盐水平，并且成骨细胞 FAM20C 介导的磷酸化调节骨形成和吸收。在这里，我们使用 Fam20C-Tg 小鼠研究了 FAM20C 在牙本质中的直接作用。与野生型小鼠相比，Fam20C-Tg 小鼠的牙齿含有许多高度磷酸化的蛋白质，包括 SIBLING。在Fam20C-Tg小鼠中，早年时冠状牙本质体积减少，矿物质密度不变，而成熟时体积不变，矿物质密度升高。在这些小鼠中，各个年龄段的根部牙本质体积和矿物质密度均下降，并且在组织学上，根部牙本质具有更宽的前牙本质和异常的根尖侧牙本质，其中嵌入细胞和嗜银小管。免疫组织化学分析显示，异常的根尖侧牙本质具有骨和牙本质基质特性，并伴有成骨细胞谱系细胞。此外，在Fam20C-Tg小鼠中，对牙本质形成重要的DSPP含量在牙本质，特别是根根牙本质中减少，这可能导致主要在根根牙本质中的缺陷。牙胚肾囊下移植显示新形成的根尖牙本质复制了Fam20C-Tg小鼠的根尖异常牙本质，证实FAM20C过度表达确实导致了异常牙本质。我们的研究结果表明，牙齿中成牙本质细胞 FAM20C 介导的磷酸化可调节牙本质形成和成牙本质细胞分化。