Notch Signaling in the Regulation of TMJ Osteoarthritis

摘要颞下颌关节（TMJ）的下颌髁突软骨（MCC）骨关节炎（OA）是一种日益严重的疾病

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.