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

TMD（颞下颌关节紊乱病）影响5-10%的人口在这个国家，严重的TMD 需要手术修复TMD的病因通常很难确定，其病理生理学基础 由于下颌髁突软骨（MCC）的发育差异很大， 以及生长板或关节软骨的结构。然而，颞下颌关节发育的调节和 增长被低估了。颞下颌关节或四肢的软骨发生被认为是一个相互联系但又相互独立的过程。 在软骨内骨形成过程中由骨生成形成。继承的信息如何传递 从软骨细胞（据说在骨形成之前经历细胞死亡）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 成骨细胞出现。然而，以下关键问题仍然存在：这种细胞转化如何与骨生长联系在一起 和重塑？潜在的分子机制是什么？细胞需要哪些基因 转化？我们认为软骨形成和骨形成是一个连续的过程， 软骨细胞衍生的骨细胞（CBC）定义了MCC支的整体模式，并有助于骨形成。 通过Bmpr 1a（BMP受体1a，BMP 2和BMP 4的关键受体）和β-连环蛋白重塑。这一假设 是基于：1）从我们的实验室和其他人发表的数据表明，直接细胞转化发生在 MCC和四肢; 2）软骨细胞中Bmpr 1a或β-连环蛋白的缺失导致髁突的剧烈变化， 在生长和骨重建过程中，尽管骨细胞中任何一个基因的缺失对骨骼的生长和骨重建几乎没有影响。 骨骼模式;和3）细胞转化的分子调控高度依赖于骨骼模式。 元素、发育阶段和不同的基因。我们将使用以下高度验证此假设 相关但独立的目的：1）确定Bmpr 1a对细胞转化的分子调控， 生长和骨重建。工作假设：CBC定义了髁突的整体形态， 通过BMPR 1A在骨骼的不同元素中发挥不同的作用;和2）：为了确定分子 在生长和骨重建过程中β-连环蛋白对细胞转化的调节。工作假设：β-连环蛋白 在髁状突与四肢中，在定义骨骼模式和骨重塑方面发挥不同的作用， 与Bmpr 1a不同;和3）：确定软骨细胞如何使软骨基质脱矿并形成骨 细胞，并在体外改变与骨细胞直接相关的基因的表达谱。工作假设： 迁移的HC在去除钙化软骨和细胞转化中发挥双重作用。我们希望CBC 在Bmpr 1a和β-catenin的调控下，负责大多数软骨内骨的形成和重塑。我们 预测这种现象也发生在四肢，虽然这些基因的差异调节。整理 这个项目可能会修改目前的教条，在这个未充分研究的领域提供新的知识，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。

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.