Mechanism of BMP2 regulation of Mandibular Condylar Cartilage Growth

摘要 本研究的目的是了解骨形态发生蛋白2(BMP2)在骨质疏松症中的作用。 下颌骨髁状突软骨的生后生长、发病机制及适应性改建。长的- 申请者的学期目标(PI)是了解调节细胞生长和分化的机制 MCC.颞下颌关节紊乱症(TMD)影响着1500多万美国人，据估计 美国每年在TMD上花费数十亿美元。骨形态发生蛋白(BMPs)信号转导 对于MCC的发生和出生后的维持至关重要，而BMP信号的过度表达已经 与软骨退行性疾病有关。尽管有大量关于BMP信号的文献 在膝关节软骨中，骨形态发生蛋白在出生后生长、适应性改建和修复中的作用知之甚少。 微囊癌的发病机制。在我们的MCC加载模型中，我们发现软骨厚度增加，基质增加 软骨细胞的合成和矿化以及肥大分化增加。此外， MCC中BMP2的条件性缺失显示细胞外基质的合成和矿化减少 减少软骨细胞的肥大分化。这些数据表明，BMP2调节MCC 生长和分化。然而，基质中BMP2调节作用的潜在机制 MCC中软骨细胞的合成和肥大分化尚不清楚。 我们的全球假设是，BMP2是MCC出生后生长和适应性重塑所必需的。 我们的理解是，BMP2是细胞外基质合成、基质矿化的主要调节者 软骨细胞肥大分化。为了验证这一假设，我们提出了以下具体建议 目标： 具体目标1：确定BMP2功能丧失对MCC的影响及其机制 软骨下骨。使用具有谱系特异性BMP2缺失的转基因小鼠模型，我们将检查 骨形态发生蛋白2功能丧失对MCC和软骨下骨的影响。 特定目的2：确定TMJ负荷对幼鼠的合成代谢效应是否通过BMP2介导 发信号。我们将利用两个互补的体内小鼠加载/卸载模型，这将导致 细胞外基质矿化增加或减少，软骨细胞肥大分化。 具体目标3：BMP2功能丧失对IHH信号通路的影响。使用特定的激活剂 在体外器官培养模型中，我们将研究BMP2和IHH之间可能的串扰 MCC中调节合成代谢反应的信号转导。 更好地了解BMP2功能丧失对出生后生长和糖尿病发病机制的影响 MCC将有助于了解TMJ的疾病，并将帮助我们将新的方法转化为 重新生成运动类型。

Abstract The objective of the proposed research is to understand the role of Bone Morphogenic Protein 2 (BMP2) in the postnatal growth, pathogenesis and adaptive remodeling of mandibular condylar cartilage (MCC). The long- term goal of the applicant (PI) is to understand the mechanism regulating the growth and differentiation of MCC. Temporomandibular joint disorders (TMDs) affect over 15 million Americans and it is estimated that the United States spends billions of dollars each year on TMDs. Bone Morphogenic Proteins (BMPs) signaling is crucial for the development and postnatal maintenance of MCC, while overexpression of BMP signaling has been associated with degenerative disorders of the cartilage. Despite a wealth of literature on BMPs signaling in articular cartilage of the knee, little is known about BMPs role in postnatal growth, adaptive remodeling and pathogenesis of MCC. In our MCC loading model we found increased cartilage thickness, increased matrix synthesis and mineralization, as well as increased hypertrophic differentiation of chondrocytes. Moreover, conditional deletion of BMP2 in MCC showed decreased synthesis and mineralization of extracellular matrix and decreased hypertrophic differentiation of chondrocytes. These data suggest that BMP2 regulates MCC growth and differentiation. However, the mechanisms underlying the regulatory effects of BMP2 in the matrix synthesis and hypertrophic differentiation of chondrocytes in MCC remain unknown. Our global hypothesis is that BMP2 is required for postnatal growth and adaptive remodeling of the MCC. Our understanding is that BMP2 is the master regulator of extracellular matrix synthesis, matrix mineralization and hypertrophic differentiation of chondrocytes. To test this hypothesis, we propose the following specific aims: Specific Aim 1: To determine the effects and mechanism of BMP2 loss of function on MCC and the subchondral bone. Using a transgenic mice model with lineage specific deletion of BMP2, we will examine the outcomes of BMP2-loss-of-function on MCC and the subchondral bone. Specific Aim 2: To determine if the anabolic effect of TMJ loading in young mice is mediated through BMP2 signaling. We will utilize two complementary in vivo mice loading/unloading models, which causes either an increase or decrease in extracellular matrix mineralization and hypertrophic differentiation of chondrocytes. Specific Aim 3: The effect of BMP2 loss of function on the Ihh signaling pathway. Using specific activators and inhibitors in an ex vivo organ culture model we will investigate possible cross-talk between BMP2 and Ihh signaling in regulating anabolic response in MCC. Greater understanding of the effect of BMP2 loss-of-function on the postnatal growth and pathogenesis of MCC will aid in the understanding of the diseases of the TMJ and will help us in translating new approaches to regenerate the joint.