Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, 54896, South Korea.
Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui, P.R. China.
Sci Rep. 2020 Apr 29;10(1):7285. doi: 10.1038/s41598-020-64188-w.
Hedgehog (Hh) signaling plays a broad role in the development of many organs including bone and teeth. It is noted that sustained Hh activity in osteoblasts negatively regulates postnatal development in mice. However, it remains unknown whether Hh signaling contributes to cementum formation. In this study, to define the roles of Hh signaling in cementum formation, we analyzed two kinds of transgenic mouse models for Hh signaling activation designed by the inactivation of Suppressor of Fused (Sufu), a negative regulator of Hh signaling, (Sufu) and a forced endogenous activation of Smo (SmoM2) under the control of osteocalcin (OC) promoter-driven Cre recombinase. Interestingly, cellular cementum apposition was remarkably reduced in both mutants. Consistently, matrix formation and mineralization ability were down-regulated in OCCM-30, a cementoblast cell line, following treatment with a pharmaceutical Smo agonist. In addition, reductions in Osx expression and β-catenin activity, which are critical for cellular cementum formation, were also detected in vitro. Furthermore, the compound mutant mice designed for the stabilization of β-catenin with both Hh-Smo signaling activation in cementoblasts revealed a complete restoration of defective cellular cementum. In addition, Wnt antagonists such as Sostdc1 and Dkk1 were also induced by Smo activation and played a role in the reduction of Osx expression and β-catenin activity. Collectively, our data demonstrated that Hh signaling negatively regulates cementum apposition in a Wnt/β-catenin/Osx-dependent manner.
Hedgehog (Hh) 信号通路在许多器官的发育中发挥广泛作用，包括骨骼和牙齿。值得注意的是，成骨细胞中持续的 Hh 活性会负调控小鼠的出生后发育。然而，Hh 信号通路是否有助于牙骨质形成仍不清楚。在这项研究中，为了确定 Hh 信号通路在牙骨质形成中的作用，我们分析了两种转基 因小鼠模型，这些模型通过抑制融合抑制因子（Sufu）的失活来激活 Hh 信号通路，Sufu 是 Hh 信号通路的负调节剂，以及在骨钙蛋白（OC）启动子驱动的 Cre 重组酶控制下强制内源性激活 Smo（SmoM2）。有趣的是，两种突变体的细胞牙骨质附着都明显减少。一致地，在 OC 诱导的成牙骨质细胞系 OCCM-30 中，在用药物 Smo 激动剂处理后，基质形成和矿化能力下调。此外，还在体外检测到细胞牙骨质形成所必需的 Osx 表达和 β-连环蛋白活性的降低。此外，在成牙骨质细胞中稳定 Hh-Smo 信号通路的复合突变体小鼠中，观察到细胞牙骨质缺陷的完全恢复。此外，Smo 激活还诱导了 Wnt 拮抗剂，如 Sostdc1 和 Dkk1，它们在降低 Osx 表达和 β-连环蛋白活性方面发挥作用。总之，我们的数据表明 Hh 信号通路以 Wnt/β-连环蛋白/Osx 依赖的方式负调控牙骨质附着。
