title: RUNX2 Mutation Impairs 1α,25-Dihydroxyvitamin D3 mediated Osteoclastogenesis in Dental Follicle Cells.
abstract: 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)2D3) 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)2D3-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)2D3-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)2D3 application because 1α,25-(OH)2D3-induced RANKL activation in hDFCs is mediated principally via the RUNX2-dependent pathway.
authors.affiliation: Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: X Z
authors.initials: XZ
authors.lastname: Wang
authors.affiliation: Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Department of Stomatology, Dongzhimen Hospital Beijing University of Chinese Medicine, 5 Haiyuncang Alley, Dongcheng District, Beijing 100700, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Outpatient Center, Peking University School and Hospital of Stomatology, 37A Xishiku Street, Xicheng District, Beijing 100034, PR China.
authors.forename: W J
authors.initials: WJ
authors.lastname: Yan
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: L H
authors.initials: LH
authors.lastname: Ge
authors.affiliation: Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: S G
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D002117:Calcitriol / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism*; D003795:Dental Sac / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D009154:Mutation; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D053245:RANK Ligand; C493709:RUNX2 protein, human; C505688:TNFSF11 protein, human; D002117:Calcitriol