Sun Xiangyu, Wang Xiaozhe, Zhang Chenying, Liu Yang, Yang Xiang, Yan Wenjuan, Liu Zhongning, Wang Yixiang, Zheng Shuguo
Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, People's Republic of China.
Department of Stomatology, Dongzhimen Hospital of Beijing University of Chinese Medicine, 5 Haiyuncang Lane, Dongcheng District, Beijing 100081, People's Republic of China.
Mutagenesis. 2016 Nov;31(6):677-685. doi: 10.1093/mutage/gew039. Epub 2016 Aug 10.
RUNX2 is an important osteo-specific factor with crucial functions in bone formation and remodelling as well as resorption of teeth. Heterozygous mutation of RUNX2 can cause cleidocranial dysplasia (CCD), a systemic disease with extensive skeletal dysplasia and abnormality of tooth growth. In our study, dental follicle cells (DFCs) and periodontal ligament cells (PDLCs) were isolated, cultured and identified from one patient with CCD and compared with normal controls. This CCD patient was confirmed to have a heterozygous frameshift mutation of RUNX2 (c.514delT, p.Ser172fs) in the previous study. The results showed that the proliferation abilities of DFCs and PDLCs were both disturbed by the RUNX2 mutation in the CCD patient compared with the normal control. A co-culture system of these cells with human peripheral blood mononuclear cells was then used to investigate the effect of RUNX2 mutation on osteoclastogenesis. We found that the RUNX2 mutation in CCD reduced the expression of osteoclast-related genes, such as RUNX2, CTR, CTSK, RANKL and OPG The ability of osteoclastogenesis in DFCs and PDLCs detected by tartrate-resistant acid phosphatase staining in the co-culture system was also reduced by the RUNX2 mutation compared with the normal control. These outcomes indicate that the RUNX2 mutation disturbs the modulatory effects of DFCs and PDLCs on the differentiation of osteoclasts and osteoblasts, thereby interfering with bone remodelling. These effects may contribute in part to the pathological manifestations of retention of primary teeth and delayed eruption of permanent teeth in patients with CCD.
RUNX2是一种重要的骨特异性因子，在骨形成、重塑以及牙齿吸收过程中发挥着关键作用。RUNX2的杂合突变可导致锁骨颅骨发育不全（CCD），这是一种全身性疾病，伴有广泛的骨骼发育异常和牙齿生长异常。在我们的研究中，从一名CCD患者中分离、培养并鉴定了牙囊细胞（DFCs）和牙周膜细胞（PDLCs），并与正常对照进行比较。在先前的研究中，已证实该CCD患者存在RUNX2的杂合移码突变（c.514delT，p.Ser172fs）。结果显示，与正常对照相比，CCD患者中RUNX2突变干扰了DFCs和PDLCs的增殖能力。随后，利用这些细胞与人外周血单个核细胞的共培养系统，研究RUNX2突变对破骨细胞生成的影响。我们发现，CCD中的RUNX2突变降低了破骨细胞相关基因的表达，如RUNX2、CTR、CTSK、RANKL和OPG。与正常对照相比，共培养系统中通过抗酒石酸酸性磷酸酶染色检测到的DFCs和PDLCs的破骨细胞生成能力也因RUNX2突变而降低。这些结果表明，RUNX2突变干扰了DFCs和PDLCs对破骨细胞和成骨细胞分化的调节作用，从而干扰了骨重塑。这些影响可能部分导致了CCD患者乳牙滞留和恒牙萌出延迟的病理表现。
