Chondrocyte-derived bone cells determine the overall pattern of TMJ condyle and contribute to bone remodeling

软骨细胞衍生的骨细胞决定颞下颌关节髁的整体模式并有助于骨重塑

基本信息

批准号：
10058837
负责人：
Louis-Bruno Ruest
金额：
$ 35.27万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058837
关键词：
Adult Affect Animal Model Apoptosis Area BMP2 gene BMP4 BMPR1A gene Biological Process Biology Bone Growth Bone remodeling Cartilage Cartilage Matrix Cell Death Cell Lineage Cells Chondrocytes Chondrogenesis Country Data Defect Development Diagnosis Disease Elements Epiphysial cartilage Event Female Foundations Functional disorder Gender Genes Goals Growth Growth and Development function Hand In Vitro Incidence Inherited Joints Knowledge Lead Limb structure Link Mandible Metaphysis Molecular Morphology Operative Surgical Procedures Osteoblasts Osteogenesis Outcomes Research Pattern Phase Play Population Process Publishing Quality of life Reagent Recording of previous events Regulation Research Research Proposals Risk Role Sampling Shapes Side Skeleton Solid Structure Technical Expertise Techniques Temporomandibular Joint Temporomandibular Joint Disorders Testing United States Variant Work articular cartilage base bone bone cell bone morphogenetic protein receptors calcification cartilage cell cell transformation condylar cartilage demineralization imaging modality in vivo in vivo Model knockout animal male migration novel novel strategies prevent receptor repaired skeletal skeletal disorder theories

项目摘要

TMD (Temporomandibular joint disorders) affect 5-10% of the population in this country, with severe TMD requiring surgical repair. The cause for TMD is often hard to determine, and the pathophysiology underlying this affliction remains unclear, as the mandibular condylar cartilage (MCC) differs considerably in its development and structure from both a growth plate or an articular cartilage. However, the regulation of TMJ development and growth has been under-studied. Chondrogenesis in the TMJ or limbs has been considered a linked but separate process from osteogenesis during endochondral bone formation. How can the inherited message be transmitted from chondrocytes, which supposedly undergo cell death before bone formation, to the cells that form bone? The answer to this question may lie in recent studies indicating that a direct transformation of chondrocytes to osteoblasts occurs. Yet, the following key questions remain: how is this cell transformation linked to bone growth and remodeling? What is the underlying molecular mechanism? Which genes are required for cell transformation? We propose that chondrogenesis and osteogenesis are one continuous process in which chondrocyte-derived bone cells (CBC) define the overall pattern of MCC-ramus and contribute to bone remodeling via Bmpr1a (BMP receptor 1a, a key receptor for BMP2 and BMP4) and -catenin. This hypothesis is based on: 1) Published data from our lab and others demonstrating that direct cell transformation occurs in MCC and limbs; 2) Deleting Bmpr1a or -catenin in chondrocytes leads to drastic changes in the condyle and limbs during growth and bone remodeling, though deletion of either gene in bone cells has little impact on the skeletal pattern; and 3) The molecular regulation of cell transformation is highly dependent on the skeletal elements, developmental stage, and different genes. We will test this hypothesis using the following highly related but independent Aims: 1) To determine molecular regulation of cell transformation by Bmpr1a during growth and bone remodeling. Working hypothesis: the CBC defines the overall morphology of the condyle and limbs via BMPR1A that plays variant roles in different elements of the skeleton; and 2): To determine molecular regulation of cell transformation by -catenin during growth and bone remodeling. Working hypothesis: -catenin plays variant roles in the condyle vs. limbs in defining skeletal pattern and bone remodeling in a manner that differs from Bmpr1a; and 3): To determine how chondrocytes demineralize cartilage matrices and form bone cells ex vivo, and shift expression profiles of genes directly linked to bone cells in vitro. Working hypothesis: HCs, which migrate, play a dual role in removing calcified cartilage and cell transformation. We expect that CBC is responsible for most endochondral bone formation and remodeling, regulated by Bmpr1a and -catenin. We predict that this phenomenon also occurs in limbs, although differentially regulated by these genes. Finishing this project will likely revise the current dogma, provide new knowledge in this understudied area, and form a basis for developing novel approaches to prevent, diagnose, and treat TMD, as well as other skeletal diseases.

TMD（颞下颌关节紊乱病）影响着该国 5-10% 的人口，其中有严重的 TMD 需要手术修复的 TMD 的原因通常很难确定，并且其病理生理学也难以确定。由于下颌髁软骨 (MCC) 的发育差异很大，因此这种痛苦仍不清楚然而，颞下颌关节发育和结构的调节。颞下颌关节或四肢的软骨形成被认为是相关但独立的。软骨内骨形成过程中的成骨过程如何传递遗传信息。从据称在骨形成前经历细胞死亡的软骨细胞到形成骨的细胞？这个问题的答案可能在于最近的研究表明，软骨细胞直接转化为然而，以下关键问题仍然存在：这种细胞转化如何与骨骼生长相关。细胞的潜在分子机制是什么？我们认为软骨形成和成骨是一个连续的过程，其中软骨细胞衍生的骨细胞 (CBC) 定义了 MCC 支的整体模式并有助于骨通过 Bmpr1a（BMP 受体 1a，BMP2 和 BMP4 的关键受体）和 β-连环蛋白进行重塑该假设。基于：1) 我们实验室和其他实验室公布的数据表明，直接细胞转化发生在 MCC 和四肢；2) 删除软骨细胞中的 Bmpr1a 或 β-catenin 会导致髁突和四肢发生剧烈变化尽管删除骨细胞中的任一基因对四肢的生长和骨骼重塑影响不大骨骼模式；3) 细胞转化的分子调控高度依赖于骨骼我们将使用以下内容高度检验这一假设。相关但独立的目的： 1) 确定 Bmpr1a 在细胞转化过程中的分子调控生长和骨重塑：CBC 定义了髁突和骨的整体形态。通过在骨骼的不同元素中发挥不同作用的 BMPR1A 来识别四肢；2)：确定分子；生长和骨重塑过程中 -连环蛋白对细胞转化的调节工作假设：-连环蛋白。在定义骨骼模式和骨重塑方面，髁突与四肢发挥着不同的作用，与 Bmpr1a 不同；和 3)：确定软骨细胞如何使软骨基质脱矿并形成骨离体细胞，以及与体外骨细胞直接相关的基因的转变表达谱工作假设： HC 会迁移，在去除钙化软骨和细胞转化方面发挥双重作用。负责大多数软骨内骨形成和重塑，受 Bmpr1a 和 β-连环蛋白 We 调节。预测这种现象也发生在四肢中，尽管受到这些基因的差异调节。该项目可能会修改当前的教条，提供这一待研究领域的新知识，并形成一个为开发预防、诊断和治疗 TMD 以及其他骨骼疾病的新方法奠定了基础。