Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
J Dent Res. 2015 Jul;94(7):936-44. doi: 10.1177/0022034515578908. Epub 2015 Mar 27.
Cleidocranial dysplasia (CCD) is characterized by the runt-related transcription factor 2 (RUNX2) mutation, which results in delayed tooth eruption due to disturbed functions of dental follicle. Accumulating evidence has revealed a key regulatory circuit, including RUNX2, miR-31, and special AT-rich binding protein 2 (SATB2) acting in concert in mesenchymal stem cell homeostasis and functions. However, whether such a regulatory loop works in dental follicle cells (DFCs) remains unknown. Herein, we investigated the roles of RUNX2-miR-31-SATB2 in DFCs from patients with CCD (DFCs-CCD) to advance our understanding regarding physical tooth eruption. We identified a novel mutation on exon 5 (c.634T>G, p.T212P) in RUNX2 via exome sequencing in the CCD patient with typical clinical presentations. Compared with DFCs from healthy donors, DFCs-CCD displayed significantly lower osteogenic, osteoclast-inductive, and matrix-degrading capacities and had lower RUNX2 (a transcriptional inhibitor of miR-31), higher miR-31, and downregulated SATB2. Lower ratios of RANKL/OPG and RANKL/RANK, as well as decreased expression of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2), would lead to inactivation of osteoclasts and suppression of bone matrix remodeling in DFCs-CCD. Furthermore, the roles of the RUNX2-miR-31-SATB2 loop in DFCs-CCD were revealed by endogenous miR-31 knockdown, which resulted in increased SATB2 and RUNX2, as well as osteoclast-inductive and matrix degradation capacities. Conversely, SATB2, RUNX2, MMP9, MMP2, and osteoclast-inductive factors expression declined upon ectopic miR-31 overexpression in normal DFCs. Importantly, neonatal mice with in vivo siRUNX2 delivery exhibited less activated osteoclasts around dental follicles and delayed tooth eruption. Together, these results suggest that RUNX2 mutation/haploinsufficiency disturbs osteoclast-inductive signaling in DFCs, which may be responsible for delayed tooth eruption in CCD patients. Manipulation of the RUNX2-miR-31-SATB2 loop may be a potential way to facilitate tooth eruption in CCD patients.
颅锁骨发育不全（CCD）的特征是 runt 相关转录因子 2（RUNX2）突变，由于牙滤泡功能障碍导致牙齿延迟萌出。越来越多的证据揭示了一个关键的调节回路，包括 RUNX2、miR-31 和特殊富含 AT 的结合蛋白 2（SATB2），它们协同作用于间充质干细胞的稳态和功能。然而，这种调节回路是否在牙滤泡细胞（DFCs）中起作用尚不清楚。在此，我们研究了 RUNX2-miR-31-SATB2 在 CCD 患者的 DFCs（DFCs-CCD）中的作用，以深入了解生理性牙齿萌出。我们通过外显子组测序在具有典型临床表现的 CCD 患者中鉴定出 RUNX2 外显子 5 上的一个新突变（c.634T>G，p.T212P）。与来自健康供体的 DFCs 相比，DFCs-CCD 显示出明显较低的成骨、破骨诱导和基质降解能力，并且 RUNX2（miR-31 的转录抑制剂）较低，miR-31 较高，SATB2 下调。RANKL/OPG 和 RANKL/RANK 的比值较低，以及基质金属蛋白酶 9（MMP9）和基质金属蛋白酶 2（MMP2）的表达降低，会导致 DFCs-CCD 中的破骨细胞失活和骨基质重塑抑制。此外，通过内源性 miR-31 敲低揭示了 RUNX2-miR-31-SATB2 循环在 DFCs-CCD 中的作用，导致 SATB2 和 RUNX2 增加，以及破骨诱导和基质降解能力增强。相反，在正常 DFCs 中外源 miR-31 过表达时，SATB2、RUNX2、MMP9、MMP2 和破骨诱导因子的表达下降。重要的是，体内 siRUNX2 递送的新生小鼠牙滤泡周围的破骨细胞激活减少，牙齿萌出延迟。总之，这些结果表明 RUNX2 突变/单倍不足扰乱了 DFCs 中的破骨诱导信号，这可能是 CCD 患者牙齿延迟萌出的原因。操纵 RUNX2-miR-31-SATB2 循环可能是促进 CCD 患者牙齿萌出的一种潜在方法。
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