International Journal of Oral Science最新文献_第9页

Adult dental epithelial stem cell-derived organoids deposit hydroxylapatite biomineral 成人牙齿上皮干细胞衍生的器官组织沉积羟基磷灰石生物矿物质

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-12-07 DOI: 10.1038/s41368-023-00257-w

Hyun-Yi Kim, Victoria Cooley, Eun-Jung Kim, Shujin Li, Jong-Min Lee, Dina Sheyfer, Wenjun Liu, Ophir D. Klein, Derk Joester, Han-Sung Jung

{"title":"Adult dental epithelial stem cell-derived organoids deposit hydroxylapatite biomineral","authors":"Hyun-Yi Kim, Victoria Cooley, Eun-Jung Kim, Shujin Li, Jong-Min Lee, Dina Sheyfer, Wenjun Liu, Ophir D. Klein, Derk Joester, Han-Sung Jung","doi":"10.1038/s41368-023-00257-w","DOIUrl":"https://doi.org/10.1038/s41368-023-00257-w","url":null,"abstract":"Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. The unique function of the epithelial cells synthesizing crystallites and assembling them in a mechanically robust structure is not fully elucidated yet, partly due to limitations with in vitro experimental models. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When transplanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model to study mineralization process by dental epithelium, which can pave the way to understanding amelogenesis and developing regenerative therapy of enamel.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"1 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138564959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia. 抗成纤维细胞生长因子 23 疗法对 X 连锁低磷血症患者牙齿的影响

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-12-06 DOI: 10.1038/s41368-023-00259-8

Elis J Lira Dos Santos, Kenta Nakajima, Julien Po, Ayako Hanai, Volha Zhukouskaya, Martin Biosse Duplan, Agnès Linglart, Takashi Shimada, Catherine Chaussain, Claire Bardet

{"title":"Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia.","authors":"Elis J Lira Dos Santos, Kenta Nakajima, Julien Po, Ayako Hanai, Volha Zhukouskaya, Martin Biosse Duplan, Agnès Linglart, Takashi Shimada, Catherine Chaussain, Claire Bardet","doi":"10.1038/s41368-023-00259-8","DOIUrl":"10.1038/s41368-023-00259-8","url":null,"abstract":"Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg-1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3-7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"53"},"PeriodicalIF":14.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138487498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expert consensus on digital guided therapy for endodontic diseases. 牙髓疾病数字引导治疗专家共识。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-12-06 DOI: 10.1038/s41368-023-00261-0

Xi Wei, Yu Du, Xuedong Zhou, Lin Yue, Qing Yu, Benxiang Hou, Zhi Chen, Jingping Liang, Wenxia Chen, Lihong Qiu, Xiangya Huang, Liuyan Meng, Dingming Huang, Xiaoyan Wang, Yu Tian, Zisheng Tang, Qi Zhang, Leiying Miao, Jin Zhao, Deqin Yang, Jian Yang, Junqi Ling

{"title":"Expert consensus on digital guided therapy for endodontic diseases.","authors":"Xi Wei, Yu Du, Xuedong Zhou, Lin Yue, Qing Yu, Benxiang Hou, Zhi Chen, Jingping Liang, Wenxia Chen, Lihong Qiu, Xiangya Huang, Liuyan Meng, Dingming Huang, Xiaoyan Wang, Yu Tian, Zisheng Tang, Qi Zhang, Leiying Miao, Jin Zhao, Deqin Yang, Jian Yang, Junqi Ling","doi":"10.1038/s41368-023-00261-0","DOIUrl":"10.1038/s41368-023-00261-0","url":null,"abstract":"Digital guided therapy (DGT) has been advocated as a contemporary computer-aided technique for treating endodontic diseases in recent decades. The concept of DGT for endodontic diseases is categorized into static guided endodontics (SGE), necessitating a meticulously designed template, and dynamic guided endodontics (DGE), which utilizes an optical triangulation tracking system. Based on cone-beam computed tomography (CBCT) images superimposed with or without oral scan (OS) data, a virtual template is crafted through software and subsequently translated into a 3-dimensional (3D) printing for SGE, while the system guides the drilling path with a real-time navigation in DGE. DGT was reported to resolve a series of challenging endodontic cases, including teeth with pulp obliteration, teeth with anatomical abnormalities, teeth requiring retreatment, posterior teeth needing endodontic microsurgery, and tooth autotransplantation. Case reports and basic researches all demonstrate that DGT stand as a precise, time-saving, and minimally invasive approach in contrast to conventional freehand method. This expert consensus mainly introduces the case selection, general workflow, evaluation, and impact factor of DGT, which could provide an alternative working strategy in endodontic treatment.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"54"},"PeriodicalIF":14.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138487499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mesenchymal stem cell-derived apoptotic bodies alleviate alveolar bone destruction by regulating osteoclast differentiation and function 间充质干细胞衍生的凋亡小体通过调节破骨细胞分化和功能减轻牙槽骨破坏

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-12-01 DOI: 10.1038/s41368-023-00255-y

Xiaoyan Li, Yiyang Jiang, Xu Liu, Jingfei Fu, Juan Du, Zhenhua Luo, Junji Xu, Ujjal Kumar Bhawal, Yi Liu, Lijia Guo

{"title":"Mesenchymal stem cell-derived apoptotic bodies alleviate alveolar bone destruction by regulating osteoclast differentiation and function","authors":"Xiaoyan Li, Yiyang Jiang, Xu Liu, Jingfei Fu, Juan Du, Zhenhua Luo, Junji Xu, Ujjal Kumar Bhawal, Yi Liu, Lijia Guo","doi":"10.1038/s41368-023-00255-y","DOIUrl":"https://doi.org/10.1038/s41368-023-00255-y","url":null,"abstract":"Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells (MSCs) are essential for periodontal regeneration. However, the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs. Apoptotic bodies (ABs) are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment, thus we investigated the effects of ABs derived from MSCs on periodontitis. MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h, after which ABs were isolated from the culture supernatant using a multi-filtration system. The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption. miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects. Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p, which interferes with the function of osteoclasts. Additionally, DC-STAMP is a key regulator that mediates membrane infusion. ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes, which mediates the engulfment of ABs by pre-osteoclasts. ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts. Collectively, MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP, which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts, which in turn led to the attenuation of their differentiation and bone resorption. These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"119 47","pages":""},"PeriodicalIF":14.9,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138468963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanisms of cellular metabolic homeostasis in stem cells. 干细胞细胞代谢稳态的分子机制。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-12-01 DOI: 10.1038/s41368-023-00262-z

Xiaoyu Li, Ou Jiang, Songlin Wang

引用次数: 0

Spatiotemporal cellular dynamics and molecular regulation of tooth root ontogeny. 牙根发生的时空细胞动力学与分子调控。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-11-24 DOI: 10.1038/s41368-023-00258-9

Pengcheng Rao, Junjun Jing, Yi Fan, Chenchen Zhou

{"title":"Spatiotemporal cellular dynamics and molecular regulation of tooth root ontogeny.","authors":"Pengcheng Rao, Junjun Jing, Yi Fan, Chenchen Zhou","doi":"10.1038/s41368-023-00258-9","DOIUrl":"10.1038/s41368-023-00258-9","url":null,"abstract":"Tooth root development involves intricate spatiotemporal cellular dynamics and molecular regulation. The initiation of Hertwig's epithelial root sheath (HERS) induces odontoblast differentiation and the subsequent radicular dentin deposition. Precisely controlled signaling pathways modulate the behaviors of HERS and the fates of dental mesenchymal stem cells (DMSCs). Disruptions in these pathways lead to defects in root development, such as shortened roots and furcation abnormalities. Advances in dental stem cells, biomaterials, and bioprinting show immense promise for bioengineered tooth root regeneration. However, replicating the developmental intricacies of odontogenesis has not been resolved in clinical treatment and remains a major challenge in this field. Ongoing research focusing on the mechanisms of root development, advanced biomaterials, and manufacturing techniques will enable next-generation biological root regeneration that restores the physiological structure and function of the tooth root. This review summarizes recent discoveries in the underlying mechanisms governing root ontogeny and discusses some recent key findings in developing of new biologically based dental therapies.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"50"},"PeriodicalIF":14.9,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138434008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Titanium particles in peri-implantitis: distribution, pathogenesis and prospects 钛颗粒在种植体周围炎中的分布、发病机制及前景

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-11-23 DOI: 10.1038/s41368-023-00256-x

Long Chen, Zian Tong, Hongke Luo, Yuan Qu, Xinhua Gu, Misi Si

{"title":"Titanium particles in peri-implantitis: distribution, pathogenesis and prospects","authors":"Long Chen, Zian Tong, Hongke Luo, Yuan Qu, Xinhua Gu, Misi Si","doi":"10.1038/s41368-023-00256-x","DOIUrl":"https://doi.org/10.1038/s41368-023-00256-x","url":null,"abstract":"Peri-implantitis is one of the most important biological complications in the field of oral implantology. Identifying the causative factors of peri-implant inflammation and osteolysis is crucial for the disease’s prevention and treatment. The underlying risk factors and detailed pathogenesis of peri-implantitis remain to be elucidated. Titanium-based implants as the most widely used implant inevitably release titanium particles into the surrounding tissue. Notably, the concentration of titanium particles increases significantly at peri-implantitis sites, suggesting titanium particles as a potential risk factor for the condition. Previous studies have indicated that titanium particles can induce peripheral osteolysis and foster the development of aseptic osteoarthritis in orthopedic joint replacement. However, it remains unconfirmed whether this phenomenon also triggers inflammation and bone resorption in peri-implant tissues. This review summarizes the distribution of titanium particles around the implant, the potential roles in peri-implantitis and the prevalent prevention strategies, which expects to provide new directions for the study of the pathogenesis and treatment of peri-implantitis.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"11 5","pages":""},"PeriodicalIF":14.9,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138297488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. MLL1通过与WDR5相互作用和抑制HES1来抑制SCAPs的神经源性潜能。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-10-18 DOI: 10.1038/s41368-023-00253-0

Chen Zhang, Weilong Ye, Mengyao Zhao, Lujue Long, Dengsheng Xia, Zhipeng Fan

{"title":"MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1.","authors":"Chen Zhang, Weilong Ye, Mengyao Zhao, Lujue Long, Dengsheng Xia, Zhipeng Fan","doi":"10.1038/s41368-023-00253-0","DOIUrl":"10.1038/s41368-023-00253-0","url":null,"abstract":"Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"48"},"PeriodicalIF":14.9,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49677340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH). 在X连锁低磷血症（XLH）的Hyp小鼠模型中，硬化蛋白抗体可改善牙槽骨质量。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-10-10 DOI: 10.1038/s41368-023-00252-1

Kelsey A Carpenter, Delia O Alkhatib, Bryan A Dulion, Elizabeth Guirado, Shreya Patel, Yinghua Chen, Anne George, Ryan D Ross

{"title":"Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH).","authors":"Kelsey A Carpenter, Delia O Alkhatib, Bryan A Dulion, Elizabeth Guirado, Shreya Patel, Yinghua Chen, Anne George, Ryan D Ross","doi":"10.1038/s41368-023-00252-1","DOIUrl":"10.1038/s41368-023-00252-1","url":null,"abstract":"X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg-1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) β-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"47"},"PeriodicalIF":14.9,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41182497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis. KIF3C和ZNF513的双重杂合致病突变可引起遗传性牙龈纤维瘤病。

IF 14.9 1区医学

International Journal of Oral Science Pub Date : 2023-09-26 DOI: 10.1038/s41368-023-00244-1

Jianfan Chen, Xueqing Xu, Song Chen, Ting Lu, Yingchun Zheng, Zhongzhi Gan, Zongrui Shen, Shunfei Ma, Duocai Wang, Leyi Su, Fei He, Xuan Shang, Huiyong Xu, Dong Chen, Leitao Zhang, Fu Xiong

{"title":"Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis.","authors":"Jianfan Chen, Xueqing Xu, Song Chen, Ting Lu, Yingchun Zheng, Zhongzhi Gan, Zongrui Shen, Shunfei Ma, Duocai Wang, Leyi Su, Fei He, Xuan Shang, Huiyong Xu, Dong Chen, Leitao Zhang, Fu Xiong","doi":"10.1038/s41368-023-00244-1","DOIUrl":"10.1038/s41368-023-00244-1","url":null,"abstract":"Hereditary gingival fibromatosis (HGF) is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity. Five distinct loci related to non-syndromic HGF have been identified; however, only two disease-causing genes, SOS1 and REST, inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. Here, based on a family pedigree with 26 members, including nine patients with HGF, we identified double heterozygous pathogenic mutations in the ZNF513 (c.C748T, p.R250W) and KIF3C (c.G1229A, p.R410H) genes within the GINGF3 locus related to HGF. Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo. ZNF513, a transcription factor, binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts. Furthermore, a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513 (p.R250W) or Kif3c (p.R412H) alone do not led to clear phenotypes with gingival fibromatosis, whereas the double mutations led to gingival hyperplasia phenotypes. In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels. ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. In summary, these results demonstrate ZNF513 + KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":"15 1","pages":"46"},"PeriodicalIF":14.9,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41130359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0