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.
Highlights
Cleidocranial dysplasia (CCD; MIM 119600), a rare hereditary autosomal dominant skeletal disorder, has been demonstrated to be caused by heterozygous mutations in RUNX2 gene[1]
In contrast to the wild-type protein located in cytoplasm as well as nuclei, the mutated RUNX2 protein expressed by the CCD human dental follicle cells (hDFCs) was mainly in the cytoplasm (Fig. 2d)
Our results indicated that the diminished proliferative and osteoclastogenic capacity of hDFCs caused by the truncated RUNX2 protein contributes to the delay in permanent teeth eruption in CCD patients
Summary
Cleidocranial dysplasia (CCD; MIM 119600), a rare hereditary autosomal dominant skeletal disorder, has been demonstrated to be caused by heterozygous mutations in RUNX2 gene ( known as CBFA1, PEBP2A1, OSF2, and AML3)[1]. As an osteoblast-specific transcription factor, RUNX2, which maps to human chromosome 6p213, regulates the expression of all major osteoblast-related genes, such as osteocalcin, BSP, type I collagen and osteopontin[4,5]. It is involved in bone and cartilage development and maintenance, but is essential for osteoblast differentiation, chondrocyte maturation and osteoclastogenesis[6,7]. Heterozygous RUNX2 mutant mice exhibit significantly delayed tooth eruption caused by a time-specific lack of osteoclasts on the bone surface facing the developing tooth[10]. The effects of 1α ,25-(OH)2D3 in the bone and root resorption processes are based on its direct induction of osteoblast-mediated osteoclastogenesis[18,19]
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