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: 10302529
• 负责人: Sumit Yadav
• 金额: $ 16.4万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302529
• 关键词: ADAMTS; Actins; Affect; American; Anabolism; Antibodies; Arthralgia; BMP2 gene; Biology; Biomechanics; Bone Spur; Cartilage; Catabolism; Cells; Chondrocytes; Control Animal; Data; Degenerative polyarthritis; Development; Disease; Down-Regulation; Enzymes; Epidemic; Erinaceidae; Event; Future; Genetic Transcription; Growth Factor; Healthcare; Healthcare Systems; Homeostasis; Hypertrophy; Impairment; In Vitro; Individual; Joints; Knee; Lead; Maintenance; Mandible; Mediator of activation protein; Meniscus structure of joint; Molecular; Mus; Muscle; Notch Signaling Pathway; Pain; Pathologic; Pathway interactions; Play; Population; Prevention; Proteoglycan; Publishing; Quality of life; Regulation; Regulatory Pathway; Role; Sclerosis; Severities; Signal Pathway; Signal Transduction; Societies; Study models; Surgical Injuries; Synovitis; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Testing; Therapeutic; Therapeutic Intervention; Thick; Tissues; Transgenic Mice; United States; Up-Regulation; Woman; Work; aggrecan; arthropathies; articular cartilage; base; bone cell; cartilage degradation; cartilage development; cartilage repair; condylar cartilage; cost; disability; experimental study; in vivo; inhibitor/antagonist; insight; joint mobilization; men; mineralization; mouse model; notch protein; novel therapeutics; osteochondral tissue; overexpression; prevent; response; smoothened signaling pathway; subchondral bone; tissue degeneration

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) 下颌髁软骨 (MCC) 的骨关节炎 (OA) 是一种日益严重的疾病 这种流行病不仅影响美国，而且影响全球。 OA主要是 其特征是软骨退变、软骨下骨硬化和关节疼痛。众所周知 分解代谢酶表达和激活的改变是 OA 中观察到的关节软骨破坏的基础， 然而，促进关节软骨分解代谢的精确分子机制尚不清楚 对 OA 的分子介质也没有明确的理解。 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，Notch 细胞内结构域 1 的谱系特异性过表达 (NICD1) 小鼠在 TMJ 的 MCC 中出现加速 OA 样体征。我们进一步观察到 NICD1 过度表达会导致骨形态发生蛋白 2 (BMP2)、Indian Hedgehog (Ihh)、MMP13 上调 ADAMTS5 和蛋白聚糖 4 (PRG4) 的下调。根据这些观察，我们假设 NICD1 在成熟软骨细胞中的过度表达将调节 BMP2 信号通路，并会 随后导致 Ihh 表达改变和降解酶表达增加，这将 导致软骨断裂。为了检验这个假设，我们将：（1）确定影响和机制 NICD1 在 TMJ 骨软骨组织上谱系特异性过度表达。使用转基因小鼠 NICD1 谱系特异性过度表达模型，我们将检查其影响和机制 NICD1 过度表达会刺激 TMJ MCC 的分解代谢反应。 (2) 确定效果 阻断Notch信号通路以防止骨软骨组织退化的进展； (3)明确Notch信号调节BMP2及其降解的分子机制 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 重点解读由于 NICD1 过度表达增加而改变的 BMP2 和 Ihh 信号传导的作用 OA的发展。 拟议的项目将建立原则证明，证明 NICD1 的表达改变是早期且具有决定性的 OA发展中的一件大事。拟议的研究有可能揭示重要的新监管 控制 TMJ MCC 稳态的途径，并为疾病机制和疾病机制开辟新的见解 治疗干预。