Function of cementocytes in cellular cementum formation and resorption

牙骨质细胞在细胞牙骨质形成和吸收中的功能

• 批准号: 9890917
• 负责人: Brian Lee Foster
• 金额: $ 14.83万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890917
• 关键词: Ablation; Apical; Biology; Bone remodeling; Cell Membrane Proteins; Cells; Cementoblast; Cementocyte; Cementogenesis; Cementum Formation; Cervical; Collagen Fiber; Complex; Connective Tissue; Cytoskeleton; Data; Dental Cementum; Dentin; Deposition; Diphtheria Toxin; Dose; Endocrine; Exhibits; Experimental Models; Expression Profiling; Extracellular Matrix; Fiber; Future; Genes; Genetic; Genetic Diseases; Goals; In Vitro; Intervention; Intracellular Membranes; Knock-out; Knowledge; Life; Link; Location; Mechanics; Metabolism; Minerals; Modeling; Molecular; Mus; Orthodontic; Orthodontics; Osteoblasts; Osteoclasts; Osteocytes; Outcome; Pathologic; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Physiologic calcification; Physiological; Plant Roots; Play; Positioning Attribute; Prevention; Process; Proteomics; Regulation; Role; Root Resorption; Signal Pathway; Signal Transduction; System; TNFSF11 gene; Testing; Therapeutic; Time; Tooth Movement; Tooth root structure; Tooth structure; Transgenic Mice; Work; apical root resorption; base; bone; bone cell; cell type; clinically relevant; dentin matrix protein 1; design; experimental study; in vivo; insight; laser capture microdissection; mechanical force; mechanical load; mouse model; novel; prevent; protein expression; repaired

PROJECT SUMMARY/ABSTRACT Tooth root cementum plays an essential role in tooth attachment as part of the periodontal complex. Cementum and bone feature comparable extracellular matrix composition and mineral content, however cementum is non- innervated, avascular, and exhibits little or no physiological remodeling, growing by apposition throughout life. Cementum can be compromised by genetic conditions, periodontal diseases, or root resorption, however therapies for periodontal diseases are currently unpredictable, while those for root resorption are non-existent. Critical gaps in knowledge about cementum biology present obstacles to more effectively preventing, abrogating, and reversing periodontal diseases such as apical root resorption. Cementocytes residing in the mineralized extracellular matrix of the cellular cementum exhibit many similarities to osteocytes, mechanoresponsive cells found in bone that direct local bone remodeling based on mechanical loading. It has been speculated that cementocytes may play a regulatory role in cellular cementum formation and/or resorption as osteocytes do in bone, however, at present this question remains uninvestigated and these hypotheses have not been directly tested. Evidence for cementocyte functions in cementum formation or resorption include: 1) Cementocytes present an in vivo and in vitro expression profile parallel to osteocytes; 2) Genetic inactivation causing abnormal osteocytes and defective bone mineralization show parallel changes in cementocytes and cellular cementum; 3) Knockout of Sost in mice promotes increased bone from altered osteocyte-osteoblast signaling, and similarly expanded cellular cementum formation suggests common molecular regulation between cementocytes and cementoblasts; 4) In a model of experimentally induced apposition (EIA) in mice used to promote rapid, new cellular cementum deposition, cementocytes exhibited cellular changes and signs of activation, and proteomic analysis of cellular cementum after EIA identified increased intracellular and cell membrane proteins, evidence of cementocyte activation; and 5) Cementocytes express osteoclast signal RANKL in vitro and in vivo its expression is linked to cellular cementum resorption. We hypothesize that cementocytes function in cementum formation and resorption, and this will be tested by two specific aims: 1) Define the requirement for cementocytes in cellular cementum apposition using novel transgenic mice in a model of EIA, combined with proteomic analysis; and 2) Determine the function of cementocytes in cellular cementum resorption using transgenic mice and a mode of orthodontics -induced apical root resorption and by mechanically loading a cementocyte line in vitro for gene analysis. Future Research Plans: Experiments will provide the first definitive data on roles of cementocytes in cementum biology and begin to define molecular signaling pathways involved in cementum apposition and resorption, providing fundamental and completely novel insights into cementum biology that may have clinical relevance in periodontal diseases. Future work will focus on potential molecular interventions to prevent or reverse apical root resorption, and induce cementocytes to promote repair cementum formation.

项目总结/摘要 牙根牙骨质作为牙周复合体的一部分，在牙齿附着中起着至关重要的作用。牙骨质 和骨特征相当的细胞外基质成分和矿物质含量，然而牙骨质是非- 神经支配的，无血管的，并且表现出很少或没有生理重塑，在整个生命中通过并置生长。 然而，牙骨质可能受到遗传条件、牙周病或牙根吸收的影响 牙周病的治疗目前是不可预测的，而牙根吸收的治疗是不存在的。 关于牙骨质生物学知识的关键差距阻碍了更有效地预防，废除， 以及逆转牙周疾病如根尖吸收。牙骨质细胞位于矿化的 细胞牙骨质的细胞外基质表现出许多与骨细胞、机械反应细胞 在骨中发现，其基于机械负荷指导局部骨重建。据推测 牙骨质细胞可能在细胞牙骨质形成和/或吸收中起调节作用， 然而，目前这个问题还没有得到研究，这些假设也没有直接被证实。 测试.牙骨质细胞在牙骨质形成或吸收中的功能的证据包括：1）牙骨质细胞 呈现与骨细胞平行的体内和体外表达谱; 2）遗传失活导致异常 骨细胞和骨矿化缺陷表现为牙骨质细胞和细胞性牙骨质的平行变化; 3） 敲除小鼠中的Sost可通过改变骨细胞-成骨细胞信号传导促进骨增加， 膨胀的细胞牙骨质形成表明牙骨质细胞之间的共同分子调节， 4）在小鼠实验诱导沉积（EIA）模型中，用于促进快速、新的成牙骨质细胞， 细胞牙骨质沉积，牙骨质细胞表现出细胞变化和活化迹象， EIA后的细胞牙骨质分析鉴定出增加的细胞内和细胞膜蛋白， 5）在体外和体内， 表达与细胞牙骨质再吸收有关。我们假设牙骨质细胞在牙骨质中起作用 形成和再吸收，这将通过两个具体目标进行测试：1）定义对牙骨质细胞的要求 在EIA模型中使用新型转基因小鼠进行细胞牙骨质沉积，结合蛋白质组学 分析;和2）使用转基因小鼠确定牙骨质细胞在细胞牙骨质吸收中的功能 和一种抗肿瘤药诱导的根尖吸收模式，并通过机械加载牙骨质细胞系， 用于基因分析。未来的研究计划：实验将提供第一个关于 牙骨质生物学中的牙骨质细胞和开始定义参与牙骨质的分子信号通路 并置和吸收，提供了基本的和完全新颖的见解牙骨质生物学， 在牙周病中具有临床相关性。未来的工作将集中在潜在的分子干预， 防止或逆转根尖吸收，诱导牙骨质细胞促进修复牙骨质形成。