Dental follicle cells participate in tooth eruption via the RUNX2-MiR-31-SATB2 loop

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. © international & american associations for dental research 2015.