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Cleidocranial dysplasia (CCD), a skeletal disorder characterized by delayed permanent tooth eruption and other dental abnormalities, is caused by heterozygous  RUNX2  mutations. As an osteoblast-specific transcription factor,  RUNX2  plays a role in bone remodeling, tooth formation and tooth eruption. To investigate the crosstalk between  RUNX2  and 1α,25-dihydroxyvitamin D3 (1α,25-(OH) 2 D 3 ) in human dental follicle cells (hDFCs) during osteoclast formation, we established a co-culture system of hDFCs from CCD patient and healthy donors with peripheral blood mononuclear cells (PBMCs). Expression of the osteoclast-associated genes and the number of TRAP +  cells were reduced in CCD hDFCs, indicating its suppressed osteoclast-inductive ability, which was reflected by the downregulated RANKL/OPG ratio. In addition, 1α,25-(OH) 2 D 3 -stimulation elevated the expression of osteoclast-related genes, as well as  RANKL  mRNA levels and RANKL/OPG ratios in control hDFCs. Conversely,  RUNX2  mutation abolished this 1α,25-(OH) 2 D 3 -induced  RANKL  gene activation and osteoclast formation in CCD hDFCs. Therefore,  RUNX2  haploinsufficiency impairs dental follicle-induced osteoclast formation capacity through RANKL/OPG signaling, which may be partially responsible for delayed permanent tooth eruption in CCD patients. Furthermore, this abnormality was not rescued by 1α,25-(OH) 2 D 3  application because 1α,25-(OH) 2 D 3 -induced RANKL activation in hDFCs is mediated principally via the  RUNX2 -dependent pathway.

RUNX2 Mutation Impairs 1α,25-Dihydroxyvitamin D3 mediated Osteoclastogenesis in Dental Follicle Cells