Notch Signaling in the Regulation of TMJ Osteoarthritis

Notch 信号传导在颞下颌关节骨关节炎的调节中

• 批准号: 10876539
• 负责人: Sumit Yadav
• 金额: $ 13.4万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10876539
• 关键词: Notch; Signaling; Regulation; TMJ; Osteoarthritis

Osteoarthritis (OA) of mandibular condylar cartilage (MCC) of the Temporomandibular Joint (TMJ) is a growing epidemic that afflicts men and women not only in United States but across the globe. OA is primarily characterized by cartilage degeneration, subchondral bone sclerosis and joint pain. It is well established that altered expression and activation of catabolic enzymes underlies the joint cartilage destruction observed in OA, however the precise molecular mechanisms responsible for promoting joint cartilage catabolism is not well understood, nor is there a defined understanding of the molecular mediators of OA. Notch signaling pathway has been identified as a potential regulator of both catabolic and anabolic mediators of OA. In our preliminary experiments, the lineage specific over expression of Notch Intracellular Domain 1 (NICD1) in mice developed accelerated OA like signs in the MCC of TMJ. We further observed that with NICD1 over expression there is upregulation of bone morphogenetic protein 2 (BMP2), Indian hedgehog (Ihh), MMP13 and ADAMTS5 and down regulation of proteoglycan 4 (PRG4). Based on these observations, we hypothesize that NICD1 over expression in mature chondrocytes will modulate the BMP2 signaling pathways and will subsequently lead altered expression of Ihh and increased expression of degradative enzymes, which will result in cartilage breakdown. To test this hypothesis, we will: (1) Determine the effects and mechanism of lineage-specific over expression of NICD1 on the osteochondral tissue of the TMJ. Using a transgenic mice model of lineage specific over expression of NICD1, we will examine the effects and the mechanism by which NICD1 over expression stimulates the catabolic responses in the MCC of TMJ. (2) Determine the effects of blocking the notch signaling pathway in preventing the progression of osteochondral tissue degeneration and; (3) Define the molecular mechanism by which notch signaling regulates the BMP2 and the degradative enzymes. Utilizing in vitro and in vivo experimental study models and inhibitors of different pathways, we will focus on deciphering the role of altered BMP2 and Ihh signaling due to increase over expression of NICD1 in the development of OA. The proposed project will establish proof of principle that the altered expression of NICD1 is early and decisive event in the development of OA. The proposed studies have the potential to reveal important new regulatory pathways that controls homeostasis of the MCC of TMJ and open new insight on disease mechanisms and therapeutic interventions.

颞下颌关节（TMJ）的下颌do骨软骨（MCC）的骨关节炎（OA）是一个增长 流行病不仅在美国而且在全球范围内都困扰着男人和女人。 OA主要是 其特征是软骨变性，软骨下骨硬化和关节疼痛。已经确定了 分解代谢酶的表达和激活的改变是在OA中观察到的关节软骨破坏的基础 但是，负责促进关节软骨分解代谢的精确分子机制不是很好 理解，也没有对OA分子介质的明确理解。 Notch信号通路已被确定为分解代谢和合成代谢介质的潜在调节剂 OA。在我们的初步实验中，特定于Notch细胞内结构域1的谱系特定于表达 （NICD1）在TMJ的MCC中，小鼠在MCC中产生了加速的OA。我们进一步观察到了NICD1 过度表达存在骨形态发生蛋白2（BMP2），印度刺猬（IHH），MMP13的上调 蛋白聚糖4（PRG4）的ADAMTS5及向下调节。基于这些观察，我们假设 成熟软骨细胞中表达的NICD1将调节BMP2信号通路，将会 随后导致IHH表达的改变和降解酶的表达增加，这将 导致软骨崩溃。为了检验该假设，我们将：（1）确定 谱系特定于TMJ的骨软骨组织上NICD1的表达。使用转基因小鼠 谱系特定于NICD1表达的模型，我们将检查效果和机制 过度表达的NICD1刺激TMJ MCC中的分解代谢反应。 （2）确定 阻止缺口信号通路，以防止骨软骨组织变性的进展； （3）定义Notch信号调节BMP2和降解的分子机制 酶。利用体外和体内实验研究模型和不同途径的抑制剂，我们将 专注于破译由于NICD1的表达增加而导致的BMP2和IHH信号改变的作用 OA的发展。 拟议的项目将建立原则的证据，即NICD1的表达改变是早期和决定性的 OA开发的事件。拟议的研究有可能揭示重要的新调节 控制TMJ MCC的稳态并开放有关疾病机制和开放的新见解的途径 治疗干预措施。