Mechanism of BMP2 regulation of Mandibular Condylar Cartilage Growth

BMP2调控下颌髁软骨生长的机制

• 批准号: 10093636
• 负责人: Sumit Yadav
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093636
• 关键词: Affect; American; Cartilage; Cartilage Diseases; Chondrocytes; Data; Degenerative Disorder; Development; Differentiation and Growth; Extracellular Matrix; Goals; Growth; Joints; Knee; Knowledge; Literature; Maintenance; Mandible; Mandibular Diseases; Mediating; Modeling; Mus; Natural regeneration; Organ Culture Techniques; Outcome; Pathogenesis; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Temporomandibular Joint; Temporomandibular Joint Disorders; Testing; Thick; Transgenic Mice; Translating; United States; articular cartilage; bone loss; bone morphogenic protein; condylar cartilage; in vivo; inhibitor/antagonist; loss of function; mineralization; mouse model; novel strategies; overexpression; postnatal; response; subchondral bone

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.

摘要 这项研究的目的是了解骨形态发生蛋白2（BMP 2）在骨形成中的作用。 下颌髁突软骨（MCC）的生后生长、发病机制和适应性重塑。很长的- 申请人（PI）的长期目标是了解调节生长和分化的机制， MCC。颞下颌关节紊乱病（TMD）影响超过1500万美国人，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）信号传导是 对于MCC的发育和出生后的维持至关重要，而BMP信号的过度表达 与软骨退化性疾病有关。尽管有大量关于BMP信号传导的文献， 在膝关节软骨中，关于BMP在出生后生长、适应性重塑和 MCC的发病机制。在我们的MCC负载模型中，我们发现软骨厚度增加，基质增加 合成和矿化，以及软骨细胞的肥大分化增加。此外，委员会认为， MCC中BMP 2的条件性缺失显示细胞外基质的合成和矿化减少 并降低软骨细胞的肥大分化。这些数据表明，BMP 2调节MCC 生长和分化。然而，基质中BMP 2调节作用的潜在机制 MCC中软骨细胞合成和肥大分化仍不清楚。 我们的总体假设是BMP 2是出生后生长和MCC适应性重塑所必需的。 我们的理解是，BMP 2是细胞外基质合成、基质矿化 和软骨细胞的肥大分化。为了验证这一假设，我们提出了以下具体的 目的： 具体目标1：确定BMP 2功能丧失对MCC的影响和机制，以及对MCC的影响。 软骨下骨我们将使用具有谱系特异性BMP 2缺失的转基因小鼠模型， MCC和软骨下骨的BMP 2功能丧失的结果。 具体目标2：确定年轻小鼠TMJ负荷的合成代谢作用是否通过BMP 2介导 信号我们将利用两种互补的体内小鼠加载/卸载模型，其导致 增加或减少细胞外基质矿化和软骨细胞肥大分化。 具体目标3：BMP 2功能丧失对Ihh信号通路的影响。使用特定的激活剂 和抑制剂在离体器官培养模型中，我们将研究BMP 2和Ihh之间可能的串扰 在MCC中调节合成代谢反应的信号传导。 更深入地了解BMP 2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疾病，并将帮助我们翻译新的方法， 使关节再生。