Integrin Function in Cartilage

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the basic mechanisms by which signals generated through integrin receptors regulate chondrocyte function. The overall hypothesis driving this work is that changes in the cartilage extracellular matrix (ECM), including production of ECM protein fragments, are recognized by chondrocyte integrins and initiate a cascade of events intended to remodel the ECM but which in arthritis result in further matrix destruction ("chondrocytic chondrolysis"). The focus of this proposal is to determine the basic cellular mechanisms that control signals generated through the α5ß1 integrin which regulate production of catabolic mediators including cytokines and matrix metalloproteinases (MMPs). During the previous funding period, we have defined the signaling pathways that mediate MMP-13 production in response to fibronectin fragment (FN-f) stimulation of the α5ß1integrin and discovered reactive oxygen species (ROS) are necessary second messengers. Using an innovative proteomics approach we found that the MAP kinase family member JNK2 is oxidized in FN-f stimulated cells forming a Cys-SOH (sulfenic acid) intermediate. Sulfenic acid formation serves as a major mechanism by which ROS regulate cell signaling but its in chondrocyte signaling has not been investigated. In his competitive renewal, we propose to determine the mechanism by which sulfenic acid formation regulates JNK2 activity in chondrocytes. We will determine the role of JNK2 activation in OA in vivo by studying the development of surgically-induced OA in JNK2-/- mice. Finally, we will determine if HB-EGF, upregulated and released when chondrocytes are stimulated by FN-f, promotes Rac activity to activate a co-signaling pathway that augments MMP-13 expression and cartilage matrix destruction. These studies will have significant impact on the field by defining key hubs in a signaling network that mediates cartilage matrix destruction. By discovering novel mechanisms by which ROS regulate this signaling network, the information can be used to develop a unique approach to altering redox-regulated catabolic signaling networks in arthritis that targets specific protein modifications. This represents a significant advance over the general inhibition of ROS production which not proven successful in treating conditions promoted by excessive ROS, including arthritis.