Dental Follicle Cells Participate in Tooth Eruption via the RUNX2-MiR-31-SATB2 Loop.

Abstract

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.

• Authors: J Ge, S Guo, Y Fu, P Zhou, P Zhang, Y Du, M Li, J Cheng, H Jiang
• Journal: Journal of dental research (J Dent Res) Vol. 94 Issue 7 Pg. 936-44 (Jul 2015) ISSN: 1544-0591 [Electronic] United States
• PMID: 25818585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © International & American Associations for Dental Research 2015.

Chemical References

• Core Binding Factor Alpha 1 Subunit
• MIRN31 microRNA, human
• Matrix Attachment Region Binding Proteins
• MicroRNAs
• Osteoprotegerin
• RANK Ligand
• RUNX2 protein, human
• Receptor Activator of Nuclear Factor-kappa B
• SATB2 protein, human
• TNFRSF11A protein, human
• TNFRSF11B protein, human
• TNFSF11 protein, human
• Transcription Factors
• Guanine
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Thymine

Topics

• Adolescent
• Animals
• Animals, Newborn
• Bone Remodeling (physiology)
• Cells, Cultured
• Child
• Cleidocranial Dysplasia (genetics)
• Coculture Techniques
• Core Binding Factor Alpha 1 Subunit (genetics, physiology)
• Dental Sac (pathology)
• Exons (genetics)
• Gene Knockdown Techniques
• Guanine
• Haploinsufficiency (genetics)
• Humans
• Male
• Matrix Attachment Region Binding Proteins (physiology)
• Matrix Metalloproteinase 2 (analysis)
• Matrix Metalloproteinase 9 (analysis)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (physiology)
• Mutation (genetics)
• Osteoclasts (physiology)
• Osteogenesis (genetics)
• Osteoprotegerin (analysis)
• RANK Ligand (analysis)
• Receptor Activator of Nuclear Factor-kappa B (analysis)
• Thymine
• Tooth Eruption (physiology)
• Transcription Factors (physiology)