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

在这个国家，5%-10%的人患有TMD(颞颌关节紊乱症)，其中TMD非常严重 需要手术修复。TMD的病因通常很难确定，其背后的病理生理学 由于下颌骨髁状突软骨(MCC)的发育有很大的不同，其苦恼仍不清楚。 以及生长板或关节软骨的结构。然而，对TMJ发展的监管和 增长一直没有得到充分的研究。TMJ或四肢的软骨生成一直被认为是一种相互关联但独立的 软骨内成骨过程中的成骨过程。如何传递继承的消息 从软骨细胞到形成骨的细胞，据说软骨细胞在骨形成之前会经历细胞死亡？ 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 成骨细胞就会出现。然而，以下关键问题仍然存在：这种细胞转化与骨骼生长是如何联系在一起的 改建呢？潜在的分子机制是什么？细胞需要哪些基因 转型？我们认为，软骨形成和成骨是一个连续的过程，其中 软骨细胞来源的骨细胞(CBC)定义了MCC分支的总体模式，并对骨有贡献 通过BMPR1a(骨形态发生蛋白受体1a，骨形态发生蛋白2和骨形态发生蛋白4的关键受体)和-连环蛋白重塑。这一假设 基于：1)来自我们实验室的公开数据和其他证明直接细胞转化发生在 2)缺失软骨细胞中的BMPR1a或-catenin会导致髁突的剧烈变化和 四肢在生长和骨改建过程中，尽管骨细胞中这两个基因的缺失对 骨骼模式；3)细胞转化的分子调控高度依赖于骨骼 元素、发育阶段和不同的基因。我们将使用以下高度验证这一假设 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 生长和骨骼重塑。工作假设：CBC定义了髁状突的整体形态和 四肢通过BMPR1A在骨骼的不同元素中扮演不同的角色；和2)：确定分子 -连环蛋白在生长和骨改建过程中对细胞转化的调节。工作假说：-连锁素 在定义骨骼模式和骨骼重塑的方式中，在髁突和四肢中扮演不同的角色 不同于BMPR1a；和3)：确定软骨细胞如何脱钙软骨基质和形成骨 细胞外，并在体外转移与骨细胞直接相关的基因表达谱。工作假设： 迁移的HCs在去除钙化软骨和细胞转化方面起着双重作用。我们预计CBC 负责大多数软骨内骨的形成和重塑，受BMPR1a和-catenin的调节。我们 预测这种现象也发生在四肢上，尽管受这些基因的不同调控。整理 这个项目可能会修改目前的教条，在这个研究不足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.