上海交通大学学报（医学版）

上海交通大学学报(医学版), 2024, 44(6): 663-675 doi: 10.3969/j.issn.1674-8115.2024.06.001

牙颌面畸形专题

牙颌面骨畸形机制研究的现状与发展

江凌勇,

上海交通大学医学院附属第九人民医院口腔颅颌面科正颌正畸中心，上海交通大学口腔医学院，国家口腔医学中心，国家口腔疾病临床医学研究中心，上海市口腔医学重点实验室，上海市口腔医学研究所，上海 200011

Status and advances in the mechanism research on dento-maxillofacial skeletal abnormalities

JIANG Lingyong,

Centre of Craniofacial Orthodontics, Department of Oral and Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, China

通讯作者: 江凌勇（1978—），男，主任医师，博士；电子信箱：jianglingyong@sjtu.edu.cn。

编委: 瞿麟平

收稿日期: 2024-02-29   接受日期: 2024-04-01   网络出版日期: 2024-06-28

基金资助: 上海交通大学医学院“双百人”项目.  20221809
中央高校基本科研业务费专项资金.  YG2023ZD14
国家自然科学基金.  82071083.  82271006.  81870740.  81570950.  81371121.  30901698
上海市自然科学基金.  22ZR1436700
上海市科技创新行动计划国际科技合作项目/政府间国际科技合作项目.  23410713600
上海交通大学医学院附属第九人民医院交叉研究基金.  JYJC202116
上海交通大学医学院生物材料与再生医学交叉研究项目.  2022LHB02
上海交通大学医学院附属第九人民医院原创项目.  JYYC003

Corresponding authors: JIANG Lingyong, E-mail:jianglingyong@sjtu.edu.cn.

Received: 2024-02-29   Accepted: 2024-04-01   Online: 2024-06-28

作者简介 About authors

江凌勇（1978—），男，主任医师，博士；电子信箱：jianglingyong@sjtu.edu.cn。 E-mail：jianglingyong@sjtu.edu.cn。

摘要

牙颌面骨畸形发病率高、病因复杂、症状严重、诊疗困难，缺乏早期干预策略，其主要原因在于相关机制研究较少、不够深入。这类疾病主要表现为骨性畸形、牙列不齐等骨与牙的形态结构、位置关系及口颌功能异常，其中颌面骨与牙-牙周复合体是两大核心结构，分别决定了颜面美观与咬合功能。颌面骨畸形精准防治需从病因角度研究发育与致病机制，而牙列不齐等牙-牙周复合体畸形矫治则需从临床正畸应力角度研究稳态与应激改建机制，两方面机制研究均可为牙颌面骨畸形防治策略发展提供重要理论基础。既往相关研究常以突变基因与差异因子表达谱的描述为主。近年来，Cre-LoxP等条件性基因编辑技术的发展，使研究者得以在体内直观地评价单一细胞谱系中致病基因的功能，助力牙颌面骨畸形研究从表型层面向分子机制层面推进。该文梳理了国内外学者近年的研究以及笔者所在课题组的研究成果，提出牙颌面骨畸形机制研究“一体两翼”模式，即牙颌面骨畸形为“一体”，颌面骨发育与畸形致病机制为“一翼”，牙-牙周复合体稳态与应激改建机制为“另一翼”；该模式的提出旨在系统性研究疾病的发生发展，探索临床干预新思路。近年的相关研究运用前沿技术从“两翼”出发探究“一体”的机制：一方面，牙颌面骨的胚胎发育来源复杂，组成型条件性模式动物成为研究关键细胞中关键因子功能的重要新策略；另一方面，牙-牙周复合体的成体改建最为频繁，诱导型条件性模式动物为模型时程精准控制提供了技术支持。随着单细胞测序与谱系示踪技术的开发，组织特异性干细胞因其原位、特化的特征渐受青睐，越来越多的研究者开始关注其特征功能，这一发展趋势十分契合“一体两翼”的研究模式，有望加快牙颌面骨畸形的理论基础建设与应用转化。该文就牙颌面骨畸形机制“一体两翼”的研究模式进行述评。

关键词： 牙颌面骨畸形 ; 牙颌面骨发育 ; 骨稳态 ; 基因编辑 ; 组织特异性干细胞

Abstract

Dento-maxillofacial skeletal abnormalities exhibit high incidence rate, complex etiology, severe symptoms, difficult diagnosis and treatment, and lack of early intervention strategies, which is mainly due to insufficient exploration of mechanism research. These diseases are characterized by abnormal morphology, disordered mutual location and impaired function of bones and teeth, including skeletal abnormalities and malocclusion. Among them, maxillofacial bone and dento-periodontal complex are the two core structures, which respectively determine facial aesthetics and occlusal function. As for maxillofacial skeletal abnormalities, mechanism studies on skeletal development and pathogenesis are required for precise prevention and treatment. As for malocclusion, mechanism studies on homeostasis and stress remodeling are required from the perspective of orthodontics. Both mechanism studies can provide basic support for the diagnosis and treatment of dento-maxillofacial skeletal deformities. In this regard, previous studies usually focused on the expression maps of mutated genes and differential factors. In recent years, the development of conditional gene editing techniques, such as Cre-LoxP system, has enabled researchers to intuitively evaluate the function of key genes in a single cell lineage in vivo, helping to advance research on dento-maxillofacial skeletal abnormalities from phenotype level to molecular mechanism level. This review summarizes recent domestic and foreign researches on dento-maxillofacial skeletal abnormalities, as well as recent achievements of the author's team, and systematically proposes a research mode concluded as “One Centre, Two Motives”. The centre is dento-maxillofacial skeletal abnormalities. One motive is the development and pathogenic mechanisms of maxillofacial bone, and the other is the homeostasis and remodeling mechanisms of dento-periodontal complex. The research mode aims at systematical study of the pathogenesis and prognosis of diseases to explore potential therapies. Many advanced technologies have contributed to the exploration of “One Centre” through “Two Motives”: on the one hand, conditional gene editing models have provided a new strategy for studying the function of key factors in key cells in vivo; on the other hand, inducible conditional gene editing models have supported the precise control of the timeline for interventions after birth. Furthermore, with the help of single-cell sequencing and lineage tracing techniques, researchers have been focusing on tissue-specific stem cells, due to their in situ and characteristic functions. This situation is highly in line with the “One Centre, Two Motives” mode, and is benefit to shed a new insight on the theoretical researches and clinical applications of dento-maxillofacial skeletal abnormalities. The article reviews the “One Centre, Two Motives” mechanism research mode of dento-maxillofacial skeletal abnormalities.

Keywords： dento-maxillofacial skeletal abnormality ; dental and maxillofacial skeletal development ; bone homeostasis ; gene editing ; tissue-specific stem cell

PDF (3183KB) 元数据 多维度评价 相关文章 导出 EndNote| Ris| Bibtex  收藏本文

本文引用格式

江凌勇. 牙颌面骨畸形机制研究的现状与发展. 上海交通大学学报(医学版)[J], 2024, 44(6): 663-675 doi:10.3969/j.issn.1674-8115.2024.06.001

JIANG Lingyong. Status and advances in the mechanism research on dento-maxillofacial skeletal abnormalities. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2024, 44(6): 663-675 doi:10.3969/j.issn.1674-8115.2024.06.001

牙颌面畸形是世界第三大口腔疾病，临床常表现为颌面骨、牙-牙周复合体、腭部等颌面部软硬组织的形态与位置关系失调，严重影响患者颜面美观与口颌功能［1］。其中，骨畸形的病因涉及先天发育性和后天获得性因素、涵盖多种疑难病种与综合征，症状严重、诊断困难。同时，目前对骨性畸形的治疗策略主要为成年正颌-正畸联合治疗及正畸掩饰性矫治为主，而希冀在儿童青少年生长发育阶段提早干预防治骨性畸形的治疗手段有限、收效甚微［2］。究其原因，主要是牙颌面骨畸形相关机制研究较少、不够深入，尚缺乏可支持临床转化的理论基础。本文梳理近年来牙颌面骨畸形机制的国内外研究，围绕疾病特征，提出以牙颌面骨畸形为“一体”，以颌面骨发育与畸形致病机制［3］、牙-牙周复合体稳态与应激改建机制［4］为“两翼”的“一体两翼”模式；同时，随着单细胞测序与谱系示踪技术的发展，组织特异性干细胞的鉴定赋予“一体两翼”更全面、更核心的内涵，将牙颌面骨畸形的机制研究从“关键因子”递进到“表达关键因子的关键细胞”［5］，为当代牙颌面畸形精准医学的发展提供了新思路。本文就牙颌面骨畸形机制“一体两翼”研究模式的现状与发展述评如下。

1 牙颌面畸形“一体两翼”研究模式的提出

1.1 一体：牙颌面骨畸形

颅骨的形成被认为是无脊椎动物进化为脊椎动物的重要标志之一。2003年，MANZANARES等［6］进一步将“新”口腔的形成归纳其中，而人类的牙颌面骨的形成与功能建立也被认为是文明诞生的要素［7］。牙颌面骨形态结构各异，承担了不同功能；按功能差异可区分为两大重要结构：颅颌面骨与牙-牙周复合体。颅颌面骨是颜面部的基本骨架结构，决定了容貌的美观；牙-牙周复合体包含了牙的排列和牙弓的形态，决定了咬合功能和鼻唇颏形态。颌骨和牙-牙周复合体在功能上相互协同，共同承担口颌系统的功能及颜面容貌［8］。

牙颌面骨结构的异常是导致牙颌面骨畸形的直接原因。一方面，颅颌面骨畸形主要是由多种因素导致的骨发育过速或过缓，可导致颅面形态异常，颜面容貌美观受损，较重者可出现脑发育迟缓、智力异常，严重者甚至可在出生后死亡［9］。颅颌面骨畸形包括：①骨性Ⅱ类、骨性Ⅲ类错畸形等发病率较高的骨性畸形，一般由上颌骨或下颌骨矢状向发育不足或过度导致。②诸多疑难罕见综合征，如因颅缝早闭导致颅骨骨质发育不良［10］的狭颅症，可造成脑组织发育不良、损伤乃至钙化［11］。然而，目前此类骨性畸形的矫治往往仅可通过手术治疗，尚无高效的出生后早期干预策略。同时，除牙颌面综合征、疑难病种外，对于青春期出现的牙颌面骨畸形，单纯正畸干预效果不佳，手术干预需成年后进行且存在复发可能；该问题是临床上一大痛点，亟待探索早期青春期干预策略。针对这些临床瓶颈，开展颌面骨发育与畸形致病机制研究是发现其潜在干预靶点的重要策略。另一方面，牙-牙周复合体结构或相对位置关系紊乱可导致牙列不齐，发病率极高，影响患者咬合功能与口腔健康［12］。目前常通过正畸治疗矫正牙列不齐，但正畸治疗疗程漫长，正畸力不当可导致骨开窗、骨开裂等多种并发症。针对这一临床瓶颈，开展牙-牙周复合体稳态与应激改建机制研究是优化正畸牙移动速率、减少并发症的重要策略。

总之，依据牙颌面骨的结构与牙颌面骨畸形的常见临床需求可为牙颌面骨畸形这“一体”的机制研究指出2个方向——颌面骨发育与畸形致病机制研究、牙-牙周复合体稳态与应激改建机制研究（图1），以下将讨论这“两翼”研究的现状与发展。

图1

新窗口打开| 下载原图ZIP| 生成PPT

图1   牙颌面骨畸形“一体两翼”研究模式示意图

Fig 1   Schematic diagram of the “One Centre, Two Motives” research mode of dento-maxillofacial skeletal deformities


1.2 一翼：颌面骨发育与畸形致病机制研究

牙颌面组织位置毗邻，但具有不同的胚胎组织来源。如额骨与牙源性组织来源于外胚层神经嵴细胞，而顶骨则来源于中胚层，这些组织发育过程中任一环节紊乱均可导致畸形发生［7］。既往人类全外显子测序研究已发现许多牙颌面骨畸形致病基因，其功能异常可导致颌面骨发育不足、矿化不良、牙发育异常［13］，相应的全身性基因敲除小鼠的WNT信号通路、刺猬（hedgehog，HH）信号通路、视黄酸（retinoic acid，RA）信号通路、骨形态发生蛋白（bone morphogenetic protein，BMP）信号通路、信号转导和转录激活因子（signal transducer and activator of transcription，STAT）信号通路、Notch信号通路、成纤维细胞生长因子（fibroblast growth factor，FGF）信号通路等发育相关通路可受到影响，发生畸形［7］。目前，部分综合征可通过骨髓移植或靶向关键信号通路进行基因治疗，但其主要缓解免疫紊乱等造血系统症状，而对牙颌面骨畸形的治疗效果并不理想［14］。因此，尚需要开发新的靶向干预策略以达到在出生后早期改善牙颌面骨畸形症状的目的。

1.2.1 运用LacZ工具鼠展示关键因子的定位及作用

早期研究常关注关键因子或关键信号在牙颌面组织中的定位和作用，期望聚焦组织的解剖学界限，尝试局部干预。研究者运用β-半乳糖苷酶（β-galactosidase gene Z，LacZ）转基因小鼠观察关键信号分子在牙颌面部的定位（图2），并通过基因敲除模拟信号失活以验证其特定功能。轴抑制蛋白2（axis inhibition protein 2，AXIN2）与T-淋巴因子/淋巴增强因子（T-cell factor/lymphoid enhancing factor，TCF/LEF）是牙颌面部WNT信号通路调控的重要下游因子［15］。Tcf/Lef-LacZ小鼠的实验结果提示WNT信号通路在牙颌面部参与了眼、听囊、第一鳃弓、额鼻骨、口腔上皮等组织发育［15］，Axin2-LacZ小鼠的实验结果提示WNT信号通路参与了眼［16］、牙周［17］、软骨［18］、牙髓［19］等组织的发育，且Axin2-/-小鼠呈现严重颅颌面骨矿化不全表型［20］。神经胶质瘤相关癌基因锌指蛋白1（glioma-associated oncogene 1，GLI1）是音猬因子（sonic hedgehog，SHH）信号通路关键转录因子，Gli1-LacZ小鼠的实验结果提示SHH信号通路在E10.5（胚胎期第10.5天）的胚胎中定位于上颌突、下颌弓与舌弓，自E11.5后主要定位于中胚层［21］。生肌因子5（myogenic factor 5，MYF5）是SHH-GLI信号通路的关键下游因子［22］，Myf5-LacZ小鼠的实验结果提示SHH信号通路于E9.25的胚胎中在鳃弓激活，调控下颌骨的形成［23］。视黄酸效应元件（retinoic acid receptor element，RARE）是RA信号通路中与受体结合的靶序列，Rare-LacZ小鼠的实验结果提示RA信号通路于E11.5的胚胎中主要在眼、颌面部激活，且RA信号通路阻断的小鼠往往表现出颅颌面骨严重缺损的胚胎致死表型［24］。Noggin作为BMP信号通路的经典拮抗因子，Noggin-LacZ小鼠的实验结果提示BMP信号参与了矢状缝、冠状缝等颅缝，以及鼻软骨、上颌骨等部位的形成［25］。δ样蛋白1（delta-like protein 1，DLL1）是Notch信号通路的经典下游因子，Dll1-LacZ小鼠的实验结果提示Notch-DLL信号通路主要参与中胚层发育，且在人类与动物中Dll1基因功能失活均会产生颅颌面骨畸形［26］。这些现象提示许多关键信号通路特征性地参与了牙颌面骨组织的形成，但针对局部组织的特征性靶向干预策略依然不足，仍无法解决牙颌面骨畸形早期干预手段匮乏的瓶颈。

图2

新窗口打开| 下载原图ZIP| 生成PPT

图2   LacZ 工具鼠实验提示WNT信号、SHH信号、RA信号、BMP信号、Notch信号参与牙颌面组织发育形成的示意图

Fig 2   Schematic diagram of the roles of WNT signaling, SHH signaling, RA signaling, BMP signaling, and Notch signaling during dento-maxillofacial development using LacZ tool mice


1.2.2 运用Cre-LoxP体系研究牙颌面关键细胞中关键因子的功能

随着精准医学的发展，针对关键细胞的靶向干预研究为疾病特征症状的治疗提供了新思路，研究者已着眼探究致病基因导致牙颌面畸形形成的关键细胞［27］。近年来，以Cre-LoxP系统为代表的条件性基因编辑模式动物技术的发展，为研究基因功能异常导致骨畸形发生的关键细胞谱系提供了新的途径。环化重组酶（cyclization recombinant enzyme，Cre）是一种位点特异性DNA重组酶，可以识别侧翼LoxP（locus of X-over P1）序列，导致2个LoxP位点之间序列发生重组，当2个LoxP位点同向分布于同一条DNA序列中时，2个LoxP位点之间的DNA片段将被切除。因此，通过在特征标记的细胞中表达Cre，即可在此特征细胞中进行条件性的基因编辑，实现研究关键细胞中关键因子功能的实验目的。目前，神经嵴细胞（neural crest cell，NCC）的Wnt1、性别决定区Y框蛋白9（sex determining region Y box protein，Sox9）［28］，成骨细胞的配对相关同源框1（paired related homeobox 1，Prx1）、成骨相关转录因子（osterix，Osx）、骨钙蛋白（osteocalcin，Ocn）、Ⅰ型胶原蛋白A1（collagen type 1 A1，Col1a1）［3］，骨细胞的牙本质基质蛋白（dentin matrix protein 1，Dmp1）［29］，成软骨细胞的Ⅱ型胶原蛋白（collagen type 2，Col2）、真皮表达蛋白（dermis-expressed protein 1，Dermo1）［30］，破骨细胞的溶菌酶C2蛋白（lysozyme C-2，Lysm）、组织蛋白酶K（cathepsin K，Ctsk）［31］，上皮细胞的角蛋白14（cytokeratin 14，Krt14），第一鳃弓细胞的桩蛋白2（paired box protein 2，Pax2）、心脏神经嵴衍生物蛋白2（heart and neural crest derivative-expressed protein 2，Hand2）［32］，腭间充质细胞的阴离子交换蛋白2（odd-skipped related 2，Osr2）［33］等细胞谱系的关键致病基因被敲除后均可呈现出不同程度的牙颌面畸形（表1）。值得注意的是，研究者发现，在特定细胞谱系中敲除关键基因可模拟牙颌面骨畸形综合征，如在成骨细胞而非破骨细胞中STAT3信号失活可导致常染色体显性高IgE综合征（autosomal dominant hyper IgE syndrome，AD-HIES）样颅颌面骨畸形［3］，为早期靶向干预的发展提供了更为精准的修饰期望与目的细胞。但目前许多疾病模型仍停留在全基因敲除阶段，尽管通过部分体内或体外干预得到了一定的治疗效果，但对这种干预作用于何种细胞、恢复了该细胞何种功能尚无法解答。因此，在精准医学飞速发展的当下，运用条件性基因编辑动物研究疾病致病机制，是开发及优化疾病靶向干预策略的重要方向。

表1   条件性基因编辑小鼠鉴定得到的牙颌面关键细胞谱系及其相关畸形致病基因

Tab 1  Key cell lineages and related genes responsible for dento-maxillofacial abnormalities through conditional gene-edited mice

Key cell lineage (marker-Cre)GenePathwayCharacteristic of abnormalitiesRelated phenotype, syndrome or diseaseReference
NCC (Wnt1-Cre)Med23WNT signaling③④Pierre Robin syndrome, micrognathia, cleft palate[35]
NCC (Wnt1-Cre)Fgf18WNT signaling①③④Micrognathia, cleft palate, hypoplastic craniofacial bones[36]
NCC (Wnt1-Cre)Six1WNT signaling, BMP signaling③④Branchio-oto-renal syndrome, micrognathia, cleft palate with ankyloglossia[37]
NCC (Wnt1-Cre)Bmp2BMP signaling③④Pierre Robin syndrome[38]
NCC (Wnt1-Cre)Bmp4BMP signaling②③④Severe deformation of molar buds, palate, and maxilla-mandibular bony structures; defected Meckel's cartilage[32]
NCC (Wnt1-Cre)Foxf2SHH signaling④Cleft palate[39]
NCC (Wnt1-Cre)Setdb1BMP signaling, WNT signaling④Cleft palate[40]
NCC (Wnt1-Cre)Ift20WNT signaling①③④Death shortly after birth due to difficulties in feeding and breathing, severe craniofacial malformation, loss of craniofacial bones, frontonasal dysplasia, micrognathia, cleft palate[41-42]
NCC (Wnt1-Cre, Sox9-Cre)G9aSHH signalingWnt1: ①③; Sox9: ①②

Wnt1: death shortly after birth, shortened maxilla, restricted airway, frontonasal dysplasia

Sox9: death shortly after birth, cranial skeletal dysplasia, smaller tooth germ, impaired tooth inner enamel epithelium

[43-45]
NCC (Wnt1-Cre)Tak1FGF signaling③④Pierre Robin syndrome, micrognathia, abnormal tongue, cleft palate[46]
NCC (Wnt1-Cre)Tgfbr2FGF signaling‒Abnormal tongue[47]
NCC (Wnt1-Cre)Nell1WNT signaling①Craniosynostosis[48]
NCC (Wnt1-Cre)Dlx3WNT signaling①③Tricho-dento-osseous syndrome, defected frontal bone and mandible[49]
NCC (Wnt1-Cre)Yap/TazWNT signaling①③Neural tube malformation, craniofacial vascular malformation, mandibular abnormalities[50]
NCC (Wnt1-Cre)Tfap2

WNT signaling,

RA signaling

①③④Branchio-oto-renal syndrome, midface cleft, defected craniofacial bone[51]
NCC (Wnt1-Cre)Twist1FGF signaling①Defected craniofacial bone[52]
NCC (Wnt1-Cre)Brca1/2P53 signaling①④Craniostenosis, cleft palate, defected craniofacial bone[53]
NCC (Wnt1-Cre)SmoSHH signaling①Defected craniofacial bone[54]
NCC (Wnt1-Cre)Ldb1WNT signaling④Cleft palate[55]
NCC (Wnt1-Cre)OsxFGF signaling①③Micrognathia, defected craniofacial bone[28]
First branchial arch mesenchymal cell (Pax2-Cre)Bmp4BMP signaling‒Bilateral hyperplastic tissues[32]
First branchial arch mesenchymal cell (Hand2-Cre)Twist1FGF signaling③④Micrognathia, cleft palate[56]
Mesenchymal cell (Twist2-Cre)Fgf18WNT signaling①③Micrognathia, defected craniofacial bone[36]
Mesenchymal cell (Twist1-Cre)Twist1FGF signaling②Defected dentin and enamel, tooth abnormalities[57]
Osteoblast (Prx1-Cre)Ift20WNT signaling①Craniostenosis[58]
Osteoblast (Osx-Cre, Col1-Cre)Fgfr3WNT signaling①

Osx: CATSHL syndrome, frontonasal dysplasia

Col1: CATSHL syndrome

[59-60]
Osteoblast (Osx-Cre)RarRA signaling①③Vitamin A deficiency, micrognathia, frontonasal dysplasia[61]
Osteoblast (Prx1-Cre, Osx-Cre)Ror2BMP signaling, STAT signaling①②③Robinow syndrome, brachyrhinia[62]
Osteoblast (Prx1-Cre, Osx-Cre)Stat3STAT signaling①③AD-HIES syndrome, defected craniofacial bone[3,63]
Osteoblast/chondroblast (Dermo1-Cre, Col2a1-Cre, Prx1-Cre, Osx-Cre)CbfbWNT signaling①②③

Dermo1 & Col2a1: Cleidocranial dysostosis, hypomineralized craniofacial bones, clavicle dysplasia

Prx1: Cleidocranial dysostosis, hypomineralized parietal bones, clavicle missing

Osx: Cleidocranial dysostosis, hypomineralized parietal bones, tooth deformities

[30,64-65]
Osteoblast/chondroblast (Prx1-Cre, Col2-Cre)Recql4P53 signaling①②Rothmund-Thomson syndrome, Baller-Gerold syndrome[66]
Chondroblast (Col2-Cre)Yap/TazWNT signaling①④Defected craniofacial bone, cleft palate[67]
Osteoblast (Ocn-Cre)WlsWNT signaling①③Defected craniofacial bone, molar deformity[68]
Osteoblast (Ocn-Cre)Ift20WNT signaling①Osteopenia-like phenotypes in skulls[42]
Osteoblast (Osx-Cre)Notch2Notch signaling①②③Hajdu-Cheney syndrome[69-70]
Osteoblast (Osx-Cre)Fgfr2FGF signaling①②③Crouzon syndrome[71-72]
Osteoblast (Prrx1-Cre)GαRANKL signaling①Fibrous dysplasia[73]
Osteoblast (Osx-Cre)Efnb1Unclear①③Larger cranial height, larger interorbital and nasal widths, smaller maxillary width[74]
Osteoblast (Osx-Cre)Atg5MMP signaling①Defected craniofacial bone[75]
Osteoblast (Osx-Cre)Fip200MMP signaling①Defected craniofacial bone[75]
Epithelial cell (Krt14-Cre、Eiia-Cre)Wnt10aWNT signaling②Taurodontism[76]
Epithelial cell (Krt14-Cre)Tgfbr2WNT signaling④Soft palate cleft[77]
Epithelial cell (Krt14-Cre)Dlx3WNT signaling②Hypomineralized enamel[78]
Epithelial cell (Krt14-Cre)Fgfr2FGF signaling②Retarded tooth formation, cleft palate[79]
Epithelial cell (Shh-Cre)WlsWNT signaling②Defective ameloblast and odontoblast differentiation[76]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)β-cateninWNT signaling④Cleft palate[80]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)Runx2RA signaling④Cleft palate[33]
Pharyngeal endoderm cell (Foxg1-Cre)Tbx1Unclear①③Velo-cardio-facial syndrome[81]

Note: ①—parietal/frontal bone abnormality; ②—dental abnormality; ③—jaw abnormality; ④—cleft palate. “‒” represents not ① or ② or ③ or ④. Prrx1—paired related homeobox 1; Foxg1—forkhead box protein G1; Med23—mediator complex subunit 23; Foxf2—forkhead box protein F2; Setdb1—SET domain, bifurcated 1; Ift20—intraflagellar transport protein 20; G9a—histone-lysine N-methyltransferase G9a; Tak1—transforming growth factor-beta-activated kinase 1; Tgfbr2—transforming growth factor, beta receptor Ⅱ; Nell1—NEL-like protein 1; Dlx3—distal-less homeobox 3; Yap/Taz—Yes-associated protein/tafazzin; Tfap2—transcription factor activating enhancer binding protein 2; Brca1/2—breast cancer susceptibility gene 1/2; Smo—smoothened, frizzled class receptor; Fgfr3—fibroblast growth factor receptor 3; Rar—retinoic acid receptor; Ror2—receptor tyrosine kinase like orphan receptor 2; Cbfb—core binding factor beta; Recql4—RecQ like helicase 4; Wls—wntless WNT ligand secretion mediator; Gα—G protein alpha; Efnb1—ephrin B1; Atg5—autophagy related protein 5; Fip200—focal adhesion kinase family interacting protein of 200 000; Tbx1—T-box protein 1; CATSHL syndrome—camptodactyly, tall stature, and hearing loss syndrome.

新窗口打开| 下载CSV


然而，这一技术模式在牙颌面骨畸形研究领域的应用存在局限性：许多标志物均沿用经典的长骨标志物，许多已建立的条件性基因编辑动物仅研究了长骨或椎骨的表型而未涉及牙颌面组织的表型［27］。并且，由于牙颌面骨与长骨发育来源并不相同［7］，因此标记的细胞谱系并不精准。同时，这些标志物本身特异性欠佳，如OSX不仅标记成骨谱系细胞，还可标记成脂细胞、血管周细胞等［34］；尽管部分下游信号已被揭示、可作为潜在靶点，但相应干预策略依然存在脱靶等风险。因此，亟需鉴定更特异的、更精准的牙颌面组织特异性干细胞标志物。

1.3 另一翼：牙-牙周复合体稳态与应激改建机制研究

发育后期开始，牙颌面骨长期的适应性改建与稳态的维持是保持口腔健康的关键，创伤性、应力性、炎症性、增龄性、内分泌等因素均可导致稳态失衡，造成牙周炎、骨质疏松等疾病［82］。其中，牙槽骨是人类全部骨骼中改建最为频繁的，其功能状态既可反映全身骨健康状态，又可反映口颌功能状态［4］。

1.3.1 应力是牙颌面组织最常见的应激反应

应力是牙颌面组织最常见的应激反应，以应力为核心机制的正畸牙移动、颌骨牵张成骨是牙颌面畸形矫治的重要手段［83］。研究发现，适当的咬合应力可有效维持牙槽骨骨量［84］，牵张成骨的牵张力可使颌骨的骨干细胞（skeletal stem cell，SSC）获得类神经嵴细胞潜能促进骨形成［85］；而因失牙造成的咬合刺激减弱可导致牙槽骨吸收［86］，太空失重环境会导致宇航员全身骨质流失［87］等。以上现象表明，适宜的应力微环境可能是维持牙颌面骨代谢活性进而维持骨量的关键所在。

1.3.2 牙-牙周复合体是牙颌面部应力改建的核心亚结构

牙-牙周复合体是由牙体-牙周膜-牙槽骨共同构成的复合结构，是牙颌面骨应力改建的核心亚结构［83，88］。围绕这一经典结构，既往研究常依据受力的方向，将牙槽骨分为张力侧与压力侧，依据表达谱描述应力对复合体功能的调控作用［88］。张力侧常由牙周膜牵拉产生的张应力介导成骨细胞与骨细胞Runt相关转录因子2（runt-related transcription factor 2，RUNX2）激活，进而促进COL1A1、骨桥蛋白（osteopontin，OPN）、OCN等骨形成相关蛋白表达上调；而压力侧则通过骨细胞感受压应力以及细胞交互作用激活破骨细胞功能，从而介导骨吸收［83］。然而，由于上述张力侧与压力侧发生的终末生物学过程分别主要为骨形成与骨吸收，并不一致，仅能作为功能状态评价指标，而要寻求加速骨改建速率、提升骨形成质量的临床干预策略，尚需构建体内模型从上游寻找关键靶点。

1.3.3 应力下牙-牙周复合体整体代谢水平评价模式

诱导型条件性基因编辑技术的发展规避了组成型模型的发育相关因素影响，为前述科学问题的突破提供了可能。这一技术使Cre蛋白可在特定节点入核，实现在模型建立的特定时间段内的条件性敲除，可使正畸牙移动等后天性防治技术改建牙-牙周复合体的生物学过程在体地、可视化地精准呈现。

在早期的表达谱相关研究中，研究者发现破骨细胞不能直接感受力学刺激，往往需要通过成骨谱系细胞和细胞交互作用间接调控［89］。因此，一系列成骨细胞相关的诱导型条件性基因编辑小鼠开始在牙颌面应力模型中应用。在正畸牙移动模型中，谱系示踪发现Col1+细胞发挥了重要的力感应和力响应作用［90］。Col1+细胞条件性敲除Stat3（Col1CreERT2; Stat3fl/fl ）减缓了牙移动速率，并通过细胞自调控形式抑制成骨活性，通过抑制基质金属蛋白酶3（matrix metalloproteinase 3，MMP3）表达的形式抑制破骨活性，即整体地调控了牙-牙周复合体的应力改建活性［4］（图3）。此外，低强度脉冲超声干预既可促进牙移动过程中成骨谱系细胞功能［91］，又可通过调控肾上腺素B2（ephrinB2，EFNB2）信号介导的成骨-破骨交互作用促进破骨活性［92］。上述现象提示可以将牙-牙周复合体的代谢水平作为整体性指标进行评价研究。同时，在Col1+细胞中条件性敲除核因子κB受体激活因子配体（receptor activator of nuclear factor kappa B ligand，Rankl）可通过降低破骨细胞活性抑制应力骨改建，减缓牙移动速率，进一步证实了成骨谱系细胞的核心作用［93］，提示靶向具备力学响应能力的特征谱系细胞可能是失力后的牙颌面骨稳态维持的潜在干预策略。然而，同样地，在牙颌面部这些细胞谱系仍然沿用长骨相关标志物，亟需鉴定牙颌面部特异性的关键谱系细胞。

图3

新窗口打开| 下载原图ZIP| 生成PPT

图3   应力下牙-牙周复合体整体代谢水平评价模式的转变

Note： OPG—osteoprotegerin; M1/M2/M3—molar 1/2/3; ROI—region of interest.

Fig 3   Transform of evaluation of the general metabolic level of tooth-periodontal complex under stress


综上，目前牙颌面骨畸形的机制研究一方面围绕致病基因与相关机制，旨在探索新的预防诊断与早期干预策略；另一方面围绕稳态下应力调控相关机制，旨在探索促进口腔健康、提升治疗效果的新策略；从而形成了“一体两翼”的研究框架。然而，目前研究聚焦的关键细胞依然主要是神经嵴细胞、成骨细胞、破骨细胞等较为宽泛、从其他系统借鉴的细胞谱系。牙颌面作为特异性极强的组织，其特异的细胞特征尚未被描述与揭示。

2 “一体两翼”的发展与展望：牙颌面组织特异性干细胞的发现

牙颌面组织成分与结构多样，既往研究围绕这些特征组织的解剖学与发育学关系发现了多种不同定位的干细胞。如神经嵴间充质来源的干细胞在牙胚形成阶段分化为牙乳头干细胞和牙囊干细胞，进一步分化为成体阶段的干细胞，根据来源不同可以分为牙髓干细胞（dental pulp stem cell，DPSC）、脱落乳牙干细胞（stem cell from human exfoliated deciduous teeth，SHED）、根尖乳头干细胞（apical papilla stem cell，SCAP）、牙囊前体细胞（dental follicle progenitor cell，DFPC）、牙周膜干细胞（periodontal ligament stem cell，PDLSC）、牙龈来源间充质干细胞（gingival mesenchymal stem cell，GMSC）等。但是，这些细胞的特征性标志物尚不清楚。

2.1 牙颌面干细胞的发现与鉴定

21世纪以来，国内外学者围绕牙颌面干细胞开展了多项研究工作。体外研究方面，施松涛团队在多个牙齿部位发现了具有干细胞特性的细胞［94］，之后持续多年聚焦在干细胞的来源与去向等命运转归研究［95］。王松灵团队聚焦在组织工程自体或异体移植PDLSC再生生物牙根，并开发临床试验新药［96］。刘怡团队关注移植后宿主免疫微环境对干细胞介导的组织再生影响［97］。金岩团队首次突破应用人乳牙干细胞再生牙髓，恢复牙髓血流和神经感觉功能［98］。以上团队大大推动了牙源性干细胞的组织工程研究和临床应用。

随着单细胞测序与谱系示踪技术的发展，研究者通过构建荧光示踪模式动物，发现了一系列牙颌面干细胞标志物：如颅骨骨缝间充质干细胞的Axin2+［99］、Prrx1+［100］、Gli1+［101］，颅骨骨膜干细胞的Mx1+ （黏病毒耐药蛋白1，myxovirus resistance 1）α-SMA+ （α-平滑肌肌动蛋白，α-smooth muscle actin）［102］，上颌窦黏膜干细胞的Krt14+Ctsk+［103］，下颌骨骨膜干细胞的Gli1+［104］、Ctsk+Ly6a+ （淋巴细胞抗原6复合物基因座A，lymphocyte antigen 6 complex locus A）［105］，PDLSC的α-SMA+［106］、Axin2+［107］、Prrx1+［108］、Gli1+［109］、Lepr+ （瘦素受体蛋白，leptin receptor）［27］、Ctsk+［27］、Pthrp+ （甲状旁腺激素相关蛋白，parathyroid hormone-related protein）［110］，DPSC的Sox10（性别决定区Y框蛋白10，sex determining region Y box protein 10）/Plp1+ （鞘磷脂脂质蛋白1，proteolipid protein 1）［111］、Cd24a+［112］，牙槽骨干细胞亚群的Fat4+ （原钙黏蛋白4，protocadherin 4）［5］、Lepr+［113］、Gli1+［114］等（图4）。上述成果通过模式动物实验进一步明确了牙颌面干细胞的特性及功能，大大推动了对牙颌面干细胞的认识。

图4

新窗口打开| 下载原图ZIP| 生成PPT

图4   牙颌面组织干细胞标志物

Fig 4   Dento-maxillofacial stem cell markers


2.2 牙颌面特征性干细胞的鉴定与展望

目前，牙颌面干细胞的鉴定大多依赖于传统的间充质干细胞标志物或发育过程中的重要基因标志，如Gli1+细胞被发现定植在血管和神经束周围，已被鉴定为小鼠切牙、颅面骨和长骨的干细胞［115］。广谱干细胞标志物的发现，一方面扩大了应用的普适性，另一方面也降低了组织效应的特异性。近年来，研究［116］发现在不同组织中存在特异的间质细胞，其功能既与它们的谱系相同，又具有独特的生理特征。此类细胞由间充质干细胞分化而来，受到组织微环境影响，可分化为特定谱系的专门间质细胞，承担组织特定的功能，具有较高的研究价值［116］。目前利用单细胞测序结合谱系示踪技术已经在胰腺［117］、动脉［118］中发现了一些在组织中承担特定功能的干细胞亚群，并基于此开展了一系列生理病理的干预措施，获得了成效。例如，研究［118］发现Sca1+（清道夫受体1，scavenger receptor 1）血管内皮祖细胞在疾病状态下形成更多血管内皮细胞，明确了Sca1+内皮祖细胞在心血管疾病模型中的作用。同时，基于椎骨组织特异性干细胞的发现，针对性开展了癌症椎骨转移的关键致病细胞与致病基因的研究，为癌症的骨转移提供了重要的理论基础［119］。但到目前为止，所发现的干细胞亚群尚未具备牙颌面组织特异性，其是否存在尚不清楚。在这一方面，柴洋团队开展了牙胚单细胞测序研究，并鉴定了关键基因，谱系示踪验证初步发现了一系列牙胚细胞标志物［120］；JIN等［5］通过对牙槽骨与长骨的单细胞测序拟合分析发现了一群牙槽骨特异性标记的Fat4+干细胞。但这2项研究成果目前均尚未得到进一步的验证。

总之，目前尚不清楚牙颌面组织特异性干细胞是否同心血管系统、胰腺、椎骨等其他系统组织中发现的特征性干细胞一样具有极强的原位组织特征功能，是否可指导特征组织形成与再生。但这一研究方向已成为牙颌面领域极具前景的前沿方向之一，通过聚焦牙颌面组织特异性干细胞关键基因功能的机制研究，开发靶向特征细胞及关键因子的药物干预策略、基于特征细胞及其生物学特征修饰的组织再生工程，有望为牙颌面骨畸形临床诊疗提供重要理论基础（图5）。

图5

新窗口打开| 下载原图ZIP| 生成PPT

图5   牙颌面骨畸形“一体两翼”研究模式的现状、发展与展望

Note：qPCR—quantitative polymerase chain reaction; WB—Western blotting; IF—immunofluorescence; IHC—immunohistochemistry; KO—knockout; cKO—conditional knockout; ScRNA-seq—single cell RNA sequencing.

Fig 5   Current status and future of the "One Centre, Two Motives" research mode for dento-maxillofacial skeletal abnormalities


3 结语

牙颌面骨畸形的病因涵盖先天发育性因素与后天获得性因素，且不同病种可呈现出截然相反的表型。这要求口腔医学临床与基础工作者逐渐提升精准预防、精准诊断、精准治疗能力，最终实现能够针对特征组织、靶向相应关键细胞及关键基因的精准医疗。“一体两翼”研究模式的提出十分契合牙颌面骨畸形机制研究的发展方向，值得研究、开展和推广。期待牙颌面骨畸形机制“一体两翼”研究模式能在未来不断推动口腔医学诊疗技术的进步，进一步造福牙颌面骨畸形患者。

作者贡献声明

江凌勇提出构思，查阅文献，撰写论文。作者阅读并同意了最终稿件的提交。

AUTHOR's CONTRIBUTIONS

JIANG Lingyong conceived the idea, retrieved literature and drafted the manuscript. The author has read the last version of paper and consented for submission.

利益冲突声明

所有作者声明不存在利益冲突。

COMPETING INTERESTS

The author discloses no conflict of interests.

参考文献

HEGGIE A A. Craniofacial disorders[J]. Aust Dent J, 2018, 63(Suppl 1): S58-S68.

[本文引用: 1]

PRUZINSKY T. Social and psychological effects of major craniofacial deformity[J]. Cleft Palate Craniofacial J, 1992, 29(6): 578-584.

[本文引用: 1]

ZHOU S R, DAI Q G, HUANG X R, et al. STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis[J]. Nat Commun, 2021, 12(1): 6891.

[本文引用: 4]

GONG X, SUN S, YANG Y, et al. Osteoblastic STAT3 is crucial for orthodontic force driving alveolar bone remodeling and tooth movement[J]. J Bone Miner Res, 2023, 38(1): 214-227.

[本文引用: 3]

JIN A, XU H, GAO X, et al. ScRNA-seq reveals a distinct osteogenic progenitor of alveolar bone[J]. J Dent Res, 2023, 102(6): 645-655.

[本文引用: 3]

MANZANARES M, NIETO M A. A celebration of the new head and an evaluation of the new mouth[J]. Neuron, 2003, 37(6): 895-898.

[本文引用: 1]

HELMS J A, SCHNEIDER R A. Cranial skeletal biology[J]. Nature, 2003, 423(6937): 326-331.

[本文引用: 4]

WILKIE A O, MORRISS-KAY G M. Genetics of craniofacial development and malformation[J]. Nat Rev Genet, 2001, 2(6): 458-468.

[本文引用: 1]

CUGURRA A, MAMULADZE T, RUSTENHOVEN J, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma[J]. Science, 2021, 373(6553): eabf7844.

[本文引用: 1]

BOK S, YALLOWITZ A R, SUN J, et al. A multi-stem cell basis for craniosynostosis and calvarial mineralization[J]. Nature, 2023, 621(7980): 804-812.

[本文引用: 1]

YU M F, MA L, YUAN Y, et al. Cranial suture regeneration mitigates skull and neurocognitive defects in craniosynostosis[J]. Cell, 2021, 184(1): 243-256.e18.

[本文引用: 1]

YEWENG S J, HUANG S F, REN L J. Orthodontics in China[J]. J Orthod, 2002, 29(1): 62-65.

[本文引用: 1]

PATIL S, RAO R S, MAJUMDAR B. Single gene disorders with craniofacial and oral manifestations[J]. J Contemp Dent Pract, 2014, 15(5): 659-671.

[本文引用: 1]

PATEL N C, GALLAGHER J L, TORGERSON T R, et al. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome[J]. J Clin Immunol, 2015, 35(5): 479-485.

[本文引用: 1]

MANI P, JARRELL A, MYERS J, et al. Visualizing canonical Wnt signaling during mouse craniofacial development[J]. Dev Dyn, 2010, 239(1): 354-363.

[本文引用: 2]

LIU B, HUNTER D J, ROOKER S, et al. Wnt signaling promotes Müller cell proliferation and survival after injury[J]. Invest Ophthalmol Vis Sci, 2013, 54(1): 444-453.

[本文引用: 1]

LIM W H, LIU B, CHENG D, et al. Wnt signaling regulates homeostasis of the periodontal ligament[J]. J Periodontal Res, 2014, 49(6): 751-759.

[本文引用: 1]

DAO D Y, YANG X, FLICK L M, et al. Axin2 regulates chondrocyte maturation and axial skeletal development[J]. J Orthop Res, 2010, 28(1): 89-95.

[本文引用: 1]

LOHI M, TUCKER A S, SHARPE P T. Expression of Axin2 indicates a role for canonical Wnt signaling in development of the crown and root during pre- and postnatal tooth development[J]. Dev Dyn, 2010, 239(1): 160-167.

[本文引用: 1]

MENG Q H, MONGAN M, WANG J J, et al. Repression of MAP3K1 expression and JNK activity by canonical Wnt signaling[J]. Dev Biol, 2018, 440(2): 129-136.

[本文引用: 1]

NAKASHIMA M, TANESE N, ITO M, et al. A novel gene, GliH1, with homology to the Gli zinc finger domain not required for mouse development[J]. Mech Dev, 2002, 119(1): 21-34.

[本文引用: 1]

GUSTAFSSON M K, PAN H, PINNEY D F, et al. Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification[J]. Genes Dev, 2002, 16(1): 114-126.

[本文引用: 1]

PATAPOUTIAN A, MINER J H, LYONS G E, et al. Isolated sequences from the linked Myf-5 and MRF4 genes drive distinct patterns of muscle-specific expression in transgenic mice[J]. Development, 1993, 118(1): 61-69.

[本文引用: 1]

LOHNES D, MARK M, MENDELSOHN C, et al. Function of the retinoic acid receptors (RARs) during development: (Ⅰ) Craniofacial and skeletal abnormalities in RAR double mutants[J]. Development, 1994, 120(10): 2723-2748.

[本文引用: 1]

YU X, KAWAKAMI H, TAHARA N, et al. Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues[J]. J Orthop Res, 2017, 35(8): 1671-1682.

[本文引用: 1]

NACKE S, SCHÄFER R, HABRÉ DE ANGELIS M, et al. Mouse mutant “rib-vertebrae” (rv): a defect in somite polarity[J]. Dev Dyn, 2000, 219(2): 192-200.

[本文引用: 1]

LI Q W, XU R S, LEI K X, et al. Insights into skeletal stem cells[J]. Bone Res, 2022, 10(1): 61.

[本文引用: 3]

BAEK W Y, KIM Y J, CROMBRUGGHE B D, et al. Osterix is required for cranial neural crest-derived craniofacial bone formation[J]. Biochem Biophys Res Commun, 2013, 432(1): 188-192.

[本文引用: 2]

XIAO M, ZHANG W J, LIU W, et al. Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment[J]. Blood, 2021, 137(25): 3533-3547.

[本文引用: 1]

QIN X, JIANG Q, MATSUO Y, et al. Cbfb regulates bone development by stabilizing Runx family proteins[J]. J Bone Miner Res, 2015, 30(4): 706-714.

[本文引用: 2]

YANG Y L, CHUNG M R, ZHOU S R, et al. STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription[J]. J Biol Chem, 2019, 294(42): 15395-15407.

[本文引用: 1]

XU J, CHEN M L, YAN Y N, et al. The effects of altered BMP4 signaling in first branchial-arch-derived murine embryonic orofacial tissues[J]. Int J Oral Sci, 2021, 13(1): 40.

[本文引用: 3]

HAN X, FENG J F, GUO T W, et al. Runx2-Twist1 interaction coordinates cranial neural crest guidance of soft palate myogenesis[J]. Elife, 2021, 10: e62387.

[本文引用: 2]

CHEN J Q, SHI Y, REGAN J, et al. Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice[J]. PLoS One, 2014, 9(1): e85161.

[本文引用: 1]

DASH S, BHATT S, FALCON K T, et al. Med23 regulates Sox9 expression during craniofacial development[J]. J Dent Res, 2021, 100(4): 406-414.

[本文引用: 1]

YUE M H, LAN Y, LIU H, et al. Tissue-specific analysis of Fgf18 gene function in palate development[J]. Dev Dyn, 2021, 250(4): 562-573.

[本文引用: 2]

LUO S Y, LIU Z X, BIAN Q, et al. Ectomesenchymal Six1 controls mandibular skeleton formation[J]. Front Genet, 2023, 14: 1082911.

[本文引用: 1]

CHEN Y X, WANG Z S, CHEN Y P, et al. Conditional deletion of Bmp2 in cranial neural crest cells recapitulates Pierre Robin sequence in mice[J]. Cell Tissue Res, 2019, 376(2): 199-210.

[本文引用: 1]

XU J Y, LIU H, LAN Y, et al. A Shh-Foxf-Fgf18-Shh molecular circuit regulating palate development[J]. PLoS Genet, 2016, 12(1): e1005769.

[本文引用: 1]

KANO S, HIGASHIHORI N, THIHA P, et al. The role of the histone methyltransferase SET domain bifurcated 1 during palatal development[J]. Biochem Biophys Res Commun, 2022, 598: 74-80.

[本文引用: 1]

NODA K, KITAMI M, KITAMI K, et al. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development[J]. Proc Natl Acad Sci U S A, 2016, 113(19): E2589-E2597.

[本文引用: 1]

YAMAGUCHI H, TERAJIMA M, KITAMI M, et al. IFT20 is critical for collagen biosynthesis in craniofacial bone formation[J]. Biochem Biophys Res Commun, 2020, 533(4): 739-744.

[本文引用: 2]

HIGASHIHORI N, LEHNERTZ B, SAMPAIO A, et al. Methyltransferase G9A regulates osteogenesis via Twist gene repression[J]. J Dent Res, 2017, 96(10): 1136-1144.

[本文引用: 1]

IDENO H, NAKASHIMA K, KOMATSU K, et al. G9a is involved in the regulation of cranial bone formation through activation of Runx2 function during development[J]. Bone, 2020, 137: 115332.

KAMIUNTEN T, IDENO H, SHIMADA A, et al. Essential roles of G9a in cell proliferation and differentiation during tooth development[J]. Exp Cell Res, 2017, 357(2): 202-210.

[本文引用: 1]

SONG Z C, LIU C, IWATA J, et al. Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development[J]. J Biol Chem, 2013, 288(15): 10440-10450.

[本文引用: 1]

HOSOKAWA R, OKA K, YAMAZA T, et al. TGF-β mediated FGF10 signaling in cranial neural crest cells controls development of myogenic progenitor cells through tissue-tissue interactions during tongue morphogenesis[J]. Dev Biol, 2010, 341(1): 186-195.

[本文引用: 1]

CHEN X Y, WANG H M, YU M L, et al. Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus[J]. Cell Death Differ, 2020, 27(4): 1415-1430.

[本文引用: 1]

DUVERGER O, OHARA T, BIBLE P W, et al. DLX3-dependent regulation of ion transporters and carbonic anhydrases is crucial for enamel mineralization[J]. J Bone Miner Res, 2017, 32(3): 641-653.

[本文引用: 1]

WANG J, XIAO Y, HSU C W, et al. Yap and Taz play a crucial role in neural crest-derived craniofacial development[J]. Development, 2016, 143(3): 504-515.

[本文引用: 1]

NGUYEN T T, MITCHELL J M, KIEL M D, et al. TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway[J]. Development, 2024, 151(1): dev202095.

[本文引用: 1]

BILDSOE H, LOEBEL D A, JONES V J, et al. Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo[J]. Dev Biol, 2009, 331(2): 176-188.

[本文引用: 1]

KITAMI K, KITAMI M, KAKU M, et al. BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development[J]. PLoS Genet, 2018, 14(5): e1007340.

[本文引用: 1]

JEONG J, MAO J H, TENZEN T, et al. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia[J]. Genes Dev, 2004, 18(8): 937-951.

[本文引用: 1]

ALMAIDHAN A, CESARIO J, LANDIN MALT A, et al. Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation[J]. BMC Dev Biol, 2014, 14: 3.

[本文引用: 1]

ZHANG Y P, BLACKWELL E L, MCKNIGHT M T, et al. Specific inactivation of Twist1 in the mandibular arch neural crest cells affects the development of the ramus and reveals interactions with Hand2[J]. Dev Dyn, 2012, 241(5): 924-940.

[本文引用: 1]

MENG T, HUANG Y Y, WANG S Z, et al. Twist1 is essential for tooth morphogenesis and odontoblast differentiation[J]. J Biol Chem, 2015, 290(49): 29593-29602.

[本文引用: 1]

YAMAGUCHI H, KITAMI M, UCHIMA KOECKLIN K H, et al. Temporospatial regulation of intraflagellar transport is required for the endochondral ossification in mice[J]. Dev Biol, 2022, 482: 91-100.

[本文引用: 1]

BIOSSE DUPLAN M, DAMBROISE E, ESTIBALS V, et al. An Fgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton[J]. Dis Model Mech, 2021, 14(4): dmm048272.

[本文引用: 1]

SUN X D, ZHANG R B, CHEN H G, et al. Fgfr3 mutation disrupts chondrogenesis and bone ossification in zebrafish model mimicking CATSHL syndrome partially via enhanced Wnt/β-catenin signaling[J]. Theranostics, 2020, 10(16): 7111-7130.

[本文引用: 1]

DAI Q, SUN S, JIN A, et al. Osteoblastic RAR inhibition causes VAD-like craniofacial skeletal deformity[J]. J Dent Res, 2023, 102(6): 667-677.

[本文引用: 1]

LEI L Z, HUANG Z W, FENG J Y, et al. Loss of receptor tyrosine kinase-like orphan receptor 2 impairs the osteogenesis of mBMSCs by inhibiting signal transducer and activator of transcription 3[J]. Stem Cell Res Ther, 2020, 11(1): 137.

[本文引用: 1]

YADAV P S, FENG S H, CONG Q, et al. Stat3 loss in mesenchymal progenitors causes Job syndrome-like skeletal defects by reducing Wnt/β-catenin signaling[J]. Proc Natl Acad Sci U S A, 2021, 118(26): e2020100118.

[本文引用: 1]

CHEN W, MA J Q, ZHU G C, et al. Cbfβ deletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfβ required for skeletal development[J]. Proc Natl Acad Sci U S A, 2014, 111(23): 8482-8487.

[本文引用: 1]

TIAN F, WU M R, DENG L F, et al. Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation[J]. J Bone Miner Res, 2014, 29(7): 1564-1574.

[本文引用: 1]

LU L C, HARUTYUNYAN K, JIN W D, et al. RECQL4 regulates p53 function in vivo during skeletogenesis[J]. J Bone Miner Res, 2015, 30(6): 1077-1089.

[本文引用: 1]

GOODWIN A F, CHEN C P, VO N T, et al. YAP/TAZ regulate elevation and bone formation of the mouse secondary palate[J]. J Dent Res, 2020, 99(12): 1387-1396.

[本文引用: 1]

LIM W H, LIU B, CHENG D, et al. Wnt signaling regulates pulp volume and dentin thickness[J]. J Bone Miner Res, 2014, 29(4): 892-901.

[本文引用: 1]

CANALIS E, GROSSMAN T R, CARRER M, et al. Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome[J]. J Biol Chem, 2020, 295(12): 3952-3964.

[本文引用: 1]

ZANOTTI S, YU J, SANJAY A, et al. Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome[J]. J Biol Chem, 2017, 292(29): 12232-12244.

[本文引用: 1]

LEE K K L, PESKETT E, QUINN C M, et al. Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse[J]. Dis Model Mech, 2018, 11(11): dmm035311.

[本文引用: 1]

KARUPPAIAH K, YU K, LIM J, et al. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth[J]. Development, 2016, 143(10): 1811-1822.

[本文引用: 1]

ZHAO X F, DENG P, IGLESIAS-BARTOLOME R, et al. Expression of an active Gαs mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance[J]. Proc Natl Acad Sci U S A, 2018, 115(3): E428-E437.

[本文引用: 1]

BEREZA S, YONG R, GRONTHOS S, et al. Craniomaxillofacial morphology in a murine model of ephrinB1 conditional deletion in osteoprogenitor cells[J]. Arch Oral Biol, 2022, 137: 105389.

[本文引用: 1]

THOMAS N, CHOI H K, WEI X X, et al. Autophagy regulates craniofacial bone acquisition[J]. Calcif Tissue Int, 2019, 105(5): 518-530.

[本文引用: 2]

XIONG Y, FANG Y, QIAN Y, et al. Wnt production in dental epithelium is crucial for tooth differentiation[J]. J Dent Res, 2019, 98(5): 580-588.

[本文引用: 2]

IWATA J I, SUZUKI A, YOKOTA T, et al. TGFβ regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate[J]. Development, 2014, 141(4): 909-917.

[本文引用: 1]

DUVERGER O, ISAAC J, ZAH A, et al. In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones[J]. J Cell Physiol, 2013, 228(3): 654-664.

[本文引用: 1]

HOSOKAWA R, DENG X M, TAKAMORI K, et al. Epithelial-specific requirement of FGFR2 signaling during tooth and palate development[J]. J Exp Zool B Mol Dev Evol, 2009, 312B(4): 343-350.

[本文引用: 1]

JANEČKOVÁ E, FENG J F, GUO T W, et al. Canonical Wnt signaling regulates soft palate development by mediating ciliary homeostasis[J]. Development, 2023, 150(5): dev201189.

[本文引用: 1]

ARNOLD J S, WERLING U, BRAUNSTEIN E M, et al. Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations[J]. Development, 2006, 133(5): 977-987.

[本文引用: 1]

KATSIMBRI P. The biology of normal bone remodelling[J]. Eur J Cancer Care, 2017, 26(6). DOI: 10.1111/ecc.12740.

[本文引用: 1]

MALTHA J C, KUIJPERS-JAGTMAN A M. Mechanobiology of orthodontic tooth movement: an update[J]. J World Fed Orthod, 2023, 12(4): 156-160.

[本文引用: 3]

SAFFAR J L, LASFARGUES J J, CHERRUAU M. Alveolar bone and the alveolar process: the socket that is never stable[J]. Periodontol 2000, 1997, 13: 76-90.

[本文引用: 1]

RANSOM R C, CARTER A C, SALHOTRA A, et al. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration[J]. Nature, 2018, 563(7732): 514-521.

[本文引用: 1]

TANNE K, NAGATAKI T, MATSUBARA S, et al. Association between mechanical stress and bone remodeling[J]. J Osaka Univ Dent Sch, 1990, 30: 64-71.

[本文引用: 1]

SIBONGA J D. Spaceflight-induced bone loss: is there an osteoporosis risk?[J]. Curr Osteoporos Rep, 2013, 11(2): 92-98.

[本文引用: 1]

JIN A, HONG Y, YANG Y, et al. FOXO3 mediates tooth movement by regulating force-induced osteogenesis[J]. J Dent Res, 2022, 101(2): 196-205.

[本文引用: 2]

XU X, LIU S Y, LIU H, et al. Piezo channels: awesome mechanosensitive structures in cellular mechanotransduction and their role in bone[J]. Int J Mol Sci, 2021, 22(12): 6429.

[本文引用: 1]

WANG X Y, HUANG X R, GAO X, et al. Differentiation potential of periodontal Col1+ cells under orthodontic force[J]. Mechanobiol Med, 2024, 2(1): 100026.

[本文引用: 1]

WANG Y J, LI J, ZHOU J P, et al. Low-intensity pulsed ultrasound enhances bone marrow-derived stem cells-based periodontal regenerative therapies[J]. Ultrasonics, 2022, 121: 106678.

[本文引用: 1]

ZHOU J, ZHU Y L, AI D Q, et al. Low-intensity pulsed ultrasound regulates osteoblast-osteoclast crosstalk via EphrinB2/EphB4 signaling for orthodontic alveolar bone remodeling[J]. Front Bioeng Biotechnol, 2023, 11: 1192720.

[本文引用: 1]

YANG C Y, JEON H H, ALSHABAB A, et al. RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement[J]. Int J Oral Sci, 2018, 10(1): 3.

[本文引用: 1]

GRONTHOS S, MANKANI M, BRAHIM J, et al. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo[J]. Proc Natl Acad Sci U S A, 2000, 97(25): 13625-13630.

[本文引用: 1]

MIURA M, GRONTHOS S, ZHAO M R, et al. SHED: stem cells from human exfoliated deciduous teeth[J]. Proc Natl Acad Sci U S A, 2003, 100(10): 5807-5812.

[本文引用: 1]

WEI F L, SONG T L, DING G, et al. Functional tooth restoration by allogeneic mesenchymal stem cell-based bio-root regeneration in swine[J]. Stem Cells Dev, 2013, 22(12): 1752-1762.

[本文引用: 1]

LIU Y, YANG R L, LIU X B, et al. Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca2+ channel sulfhydration[J]. Cell Stem Cell, 2014, 15(1): 66-78.

[本文引用: 1]

XUAN K, LI B, GUO H, et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth[J]. Sci Transl Med, 2018, 10(455): eaaf3227.

[本文引用: 1]

MARUYAMA T, JEONG J, SHEU T J, et al. Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration[J]. Nat Commun, 2016, 7: 10526.

WILK K, YEH S C A, MORTENSEN L J, et al. Postnatal calvarial skeletal stem cells expressing PRX1 reside exclusively in the calvarial sutures and are required for bone regeneration[J]. Stem Cell Reports, 2017, 8(4): 933-946.

ZHAO H, FENG J F, HO T V, et al. The suture provides a niche for mesenchymal stem cells of craniofacial bones[J]. Nat Cell Biol, 2015, 17(4): 386-396.

ORTINAU L C, WANG H, LEI K, et al. Identification of functionally distinct Mx1+αSMA+ periosteal skeletal stem cells[J]. Cell Stem Cell, 2019, 25(6): 784-796.e5.

[本文引用: 1]

WENG Y T, WANG H C, WU D, et al. A novel lineage of osteoprogenitor cells with dual epithelial and mesenchymal properties govern maxillofacial bone homeostasis and regeneration after MSFL[J]. Cell Res, 2022, 32(9): 814-830.

ZHANG N, BARRELL W B, LIU K J. Identification of distinct subpopulations of Gli1-lineage cells in the mouse mandible[J]. J Anat, 2023, 243(1): 90-99.

DING Y, MO C, GENG J, et al. Identification of periosteal osteogenic progenitors in jawbone[J]. J Dent Res, 2022, 101(9): 1101-1109.

[本文引用: 1]

ROGULJIC H, MATTHEWS B G, YANG W, et al. In vivo identification of periodontal progenitor cells[J]. J Dent Res, 2013, 92(8): 709-715.

YUAN X, PEI X, ZHAO Y, et al. A Wnt-responsive PDL population effectuates extraction socket healing[J]. J Dent Res, 2018, 97(7): 803-809.

BASSIR S H, GARAKANI S, WILK K, et al. Prx1 expressing cells are required for periodontal regeneration of the mouse incisor[J]. Front Physiol, 2019, 10: 591.

ZHAO H, FENG J F, SEIDEL K, et al. Secretion of Shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor[J]. Cell Stem Cell, 2014, 14(2): 160-173.

TAKAHASHI A, NAGATA M, GUPTA A, et al. Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption[J]. Proc Natl Acad Sci U S A, 2019, 116(2): 575-580.

[本文引用: 1]

KAUKUA N, SHAHIDI M K, KONSTANTINIDOU C, et al. Glial origin of mesenchymal stem cells in a tooth model system[J]. Nature, 2014, 513(7519): 551-554.

[本文引用: 1]

CHEN H, FU H C, WU X, et al. Regeneration of pulpo-dentinal-like complex by a group of unique multipotent CD24a+ stem cells[J]. Sci Adv, 2020, 6(15): eaay1514.

ZHANG D, ZHANG S, WANG J, et al. LepR-expressing stem cells are essential for alveolar bone regeneration[J]. J Dent Res, 2020, 99(11): 1279-1286.

SHALEHIN N, SEKI Y, TAKEBE H, et al. Gli1+-PDL cells contribute to alveolar bone homeostasis and regeneration[J]. J Dent Res, 2022, 101(12): 1537-1543.

WU L D, LIU Z X, XIAO L, et al. The role of Gli1+ mesenchymal stem cells in osteogenesis of craniofacial bone[J]. Biomolecules, 2023, 13(9): 1351.

[本文引用: 1]

BUECHLER M B, PRADHAN R N, KRISHNAMURTY A T, et al. Cross-tissue organization of the fibroblast lineage[J]. Nature, 2021, 593(7860): 575-579.

[本文引用: 2]

LI W D, CAVELTI-WEDER C, ZHANG Y Y, et al. Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells[J]. Nat Biotechnol, 2014, 32(12): 1223-1230.

[本文引用: 1]

TANG J, WANG H X, HUANG X Z, et al. Arterial Sca1+ vascular stem cells generate de novo smooth muscle for artery repair and regeneration[J]. Cell Stem Cell, 2020, 26(1): 81-96.e4.

[本文引用: 2]

SUN J, HU L L, BOK S, et al. A vertebral skeletal stem cell lineage driving metastasis[J]. Nature, 2023, 621(7979): 602-609.

[本文引用: 1]

JING J J, FENG J F, YUAN Y, et al. Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis[J]. Nat Commun, 2022, 13(1): 4803.

[本文引用: 1]

/

〈 〉