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）的下颌髁突软骨（MCC）骨关节炎（OA）是一种日益严重的 这种流行病不仅在美国，而且在地球仪各地折磨着男人和女人。OA主要是 其特征在于软骨退化、软骨下骨硬化和关节疼痛。已充分证实 分解代谢酶的改变的表达和活化是在OA中观察到的关节软骨破坏的基础， 然而，负责促进关节软骨软骨细胞增殖的精确分子机制并不清楚， 但是，对OA的分子介质也没有明确的理解。 Notch信号通路被认为是分解代谢和合成代谢的潜在调节因子 的OA。在我们的初步实验中，Notch胞内结构域1的谱系特异性过表达被抑制。 （NICD 1）的小鼠在TMJ的MCC中出现加速的OA样体征。我们进一步观察到，NICD 1 在过度表达的情况下，骨形态发生蛋白2（BMP 2）、印度刺猬蛋白（Ihh）、MMP 13 和ADAMTS 5以及蛋白聚糖4（PRG 4）的下调。基于这些观察，我们假设 NICD 1在成熟软骨细胞中的过表达将调节BMP 2信号通路， 随后导致Ihh表达改变和降解酶表达增加， 导致软骨破裂。为了验证这一假设，我们将：（1）确定的影响和机制， 在TMJ的骨软骨组织上，NICD 1的谱系特异性过表达。使用转基因小鼠 我们将研究NICD 1谱系特异性过表达的影响和机制， NICD 1过表达可刺激TMJ MCC的分解代谢反应。(2)确定影响 阻断notch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BMP 2和降解蛋白的分子机制。 内切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 重点是破译由于NICD 1过度表达增加而改变的BMP 2和Ihh信号传导的作用， OA的发展。 该项目将确立NICD 1表达改变是早期和决定性的原则证据。 在OA的发展过程中。拟议的研究有可能揭示重要的新的监管 控制TMJ MCC稳态的途径，并对疾病机制和 治疗干预。