Notch Signaling in the Regulation of TMJ Osteoarthritis

摘要颞下颌关节(TMJ)的髁状突软骨(MCC)骨性关节炎(OA)是一种增生性疾病。 不仅在美国，而且在全球范围内困扰着男人和女人的流行病。办公自动化主要是 以软骨变性、软骨下骨硬化症和关节痛为特征。众所周知， 分解代谢酶的表达和激活的改变是骨关节炎关节软骨破坏的基础， 然而，促进关节软骨分解代谢的确切分子机制还不是很清楚。 理解，也没有一个明确的理解的分子介体的OA。 Notch信号通路被认为是分解代谢和合成代谢介质的潜在调节因子。 对于办公自动化来说。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)在小鼠TMJ的MCC出现加速的OA样征象。我们进一步观察到，使用NICD1 过度表达骨形态发生蛋白2(BMP2)、印度刺猬(IHH)、MMP13 ADAMTS5和蛋白多糖4(PRG4)的下调。基于这些观察结果，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，并将 随后导致IHH的表达改变和降解酶的表达增加，这将 导致软骨破裂。为了验证这一假说，我们将：(1)确定其作用和机制 NICD1在TMJ骨软骨组织中的家族特异性过表达。使用转基因小鼠 模型，我们将研究NICD1的作用及其机制。 NICD1过表达可刺激TMJ MCC的分解代谢反应。(2)确定影响 阻断Noch信号通路，防止骨软骨组织退变的进展； (3)明确了Noch信号调节BMP2和降解物的分子机制 酵素。利用体外和体内不同途径的实验研究模型和抑制剂，我们将 重点破译因NICD1过度表达而改变的BMP2和IHH信号的作用 办公自动化的发展。 拟议的项目将建立原则证据，证明NICD1的改变表达是早期和决定性的 办公自动化发展中的重大事件。拟议中的研究有可能揭示重要的新法规 控制TMJ MCC动态平衡的途径，开启了对疾病机制和 治疗性干预。

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.