The Critical Role of MMP13 in Regulating Tooth Development and Reactionary Dentinogenesis Repair Through the Wnt Signaling Pathway.
The Critical Role of MMP13 in Regulating Tooth Development and Reactionary Dentinogenesis Repair Through the Wnt Signaling Pathway.
复制标题
DOI：
10.3389/fcell.2022.883266
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
基质金属蛋白酶-13(MMP13)在骨形成和改建中起重要作用，但其在牙齿发育中的作用尚不清楚。为了研究这一点，利用MMP13基因敲除(MMP13−/−)小鼠来分析牙本质-牙髓复合体的表型变化、矿化相关的标记表达和机制相互作用。免疫组织化学显示MMP13在发育中的WT磨牙的牙髓组织、成釉细胞、成牙本质细胞和牙本质中高表达，在成人磨牙中表达减少，而人DPC培养显示在矿化过程中MMP13的表达增加了2000倍。在形态上，MMP13−/−磨牙表现出严重的牙本质表型改变，影响牙本质小管的规律性、成牙本质细胞栅栏和前牙本质的清晰度，牙本质体积显著减小(∼30%切牙；13%磨牙)，以及釉质和牙本质矿物密度。在MMP13−/−磨牙尖端，反应性第三牙本质对损伤的反应减少，但在MMP13缺失的样本中，营养不良的牙髓矿化显著增加。体内MMP13缺失后，成牙本质细胞分化标记物Nestin和DSP的表达减少，在MMP13缺失的DPC培养中钙沉积减少。对WT和MMP13−/−纸浆的核糖核酸测序分析强调了5,020个转录本有显著的2.0倍的变化，路径分析表明WNT信号通路下调，并得到WNT反应基因Axin2体内表达减少的支持。MMP13与Axin2的相互作用可能是成牙本质细胞活性丧失以及牙齿表型和体积改变的部分原因，这在本研究中是显而易见的。总体而言，我们的新发现表明MMP13在牙齿发育和矿化过程中起关键作用，强调了与Wnt信号通路的机械相互作用。
Matrix-metalloproteinase-13 (MMP13) is important for bone formation and remodeling; however, its role in tooth development remains unknown. To investigate this, MMP13-knockout (Mmp13 −/− ) mice were used to analyze phenotypic changes in the dentin–pulp complex, mineralization-associated marker-expression, and mechanistic interactions. Immunohistochemistry demonstrated high MMP13-expression in pulp-tissue, ameloblasts, odontoblasts, and dentin in developing WT-molars, which reduced in adults, with human-DPC cultures demonstrating a >2000-fold increase in Mmp13-expression during mineralization. Morphologically, Mmp13 −/− molars displayed critical alterations in the dentin-phenotype, affecting dentin-tubule regularity, the odontoblast-palisade and predentin-definition with significantly reduced dentin volume (∼30% incisor; 13% molar), and enamel and dentin mineral-density. Reactionary-tertiary-dentin in response to injury was reduced at Mmp13 −/− molar cusp-tips but with significantly more dystrophic pulpal mineralization in MMP13-null samples. Odontoblast differentiation-markers, nestin and DSP, reduced in expression after MMP13-loss in vivo, with reduced calcium deposition in MMP13-null DPC cultures. RNA-sequencing analysis of WT and Mmp13 −/− pulp highlighted 5,020 transcripts to have significantly >2.0-fold change, with pathway-analysis indicating downregulation of the Wnt-signaling pathway, supported by reduced in vivo expression of the Wnt-responsive gene Axin2. Mmp13 interaction with Axin2 could be partly responsible for the loss of odontoblastic activity and alteration to the tooth phenotype and volume which is evident in this study. Overall, our novel findings indicate MMP13 as critical for tooth development and mineralization processes, highlighting mechanistic interaction with the Wnt-signaling pathway.
登录
查看更多内容
影响因子：
5.6
作者：
Duncan HF;Smith AJ;Fleming GJ;Partridge NC;Shimizu E;Moran GP;Cooper PR
通讯作者：
Cooper PR
影响因子：
4.3
作者：
Kutmon M;van Iersel MP;Bohler A;Kelder T;Nunes N;Pico AR;Evelo CT
通讯作者：
Evelo CT
影响因子：
2.9
作者：
Butler, WT;Brunn, JC;McKee, MD
通讯作者：
McKee, MD
影响因子：
1.9
作者：
Baba, O;Qin, CL;Butler, WT
通讯作者：
Butler, WT
影响因子：
5.2
作者：
Fong, Helen;Hohenstein, Kristi A.;Donovan, Peter J.
通讯作者：
Donovan, Peter J.