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The Role of gp130 Cytokines in Osteoarthritis

gp130 细胞因子在骨关节炎中的作用

基本信息

批准号：
9893139
负责人：
THORSTEN KIRSCH
金额：
$ 18.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893139
关键词：
Adult Affect Binding Biology Cartilage Cells Chondrocytes Ciliary Neurotrophic Factor Receptor Collagen Type II Complex Cytokine Receptors Cytokine Signaling Data Degenerative polyarthritis Development Event Exhibits Family Goals Histologic Homeostasis Human Hydrogen Peroxide IL6ST gene In Vitro Individual Inflammatory Injections Interleukin-1 beta Interleukin-6 Investigation Knee joint Lead Modeling Mus Neurons Operative Surgical Procedures Oxidative Stress Paraquat Pathogenesis Pathology Play Protective Agents Research Role Severities Signal Transduction Synovitis Testing Tissues aggrecan articular cartilage body system bone cell cartilage cell cartilage degradation cytokine glycoprotein 130 in vivo inflammatory milieu joint injury leukemia inhibitory factor receptor microCT mitochondrial dysfunction new therapeutic target novel novel therapeutics overexpression protective effect protective factors receptor regenerative subchondral bone treatment strategy

项目摘要

PROJECT SUMMARY Currently there is no treatment to stop or slow down the progression of osteoarthritis (OA) available. Therefore, the discovery of novel mechanisms or factors that protect articular chondrocytes against catabolic events and ultimately slow down cartilage degradation during OA progression is highly needed. Recently, cytokine receptor-like factor 1 (CLRF1) and cardiotrophin-like cytokine (CLC), two cytokines belonging to the IL-6 or gp130 cytokine superfamily, have become the matter of intense investigations because of their potential activities in adult biology, degenerative and regenerative conditions in a wide range of organ systems. CRLF1 can signal alone as a homodimer or as a heterodimeric complex together with CLC. More importantly, CRLF1 homodimer signaling has been show to protect neurons against oxidative stress, whereas CRLF1/CLC heterodimer signaling has been shown play major roles in adult pathologies of various tissues. Previous studies have shown that CRLF1 is being expressed by bone and cartilage cells. Very little, however, is known about the role of these two cytokines in cartilage homeostasis and OA pathology. Our exciting preliminary findings showing increased expression of CRLF1 during early stages of OA, the induction of CLC expression in articular chondrocytes under inflammatory conditions, the stimulation of catabolic events in human articular chondrocytes by the CRLF1/CLC complex, and the chondro-protective effects of CRLF1 alone supports our hypothesis that CRLF1 and CLC play important roles in cartilage homeostasis and OA pathology. Specifically, we propose that while the heterodimeric CRLF1/CLC complex stimulates catabolic events in articular chondrocytes, exogenous CRLF1 despite the presence of CLC protects chondrocytes in an inflammatory environment. To test our hypothesis we are proposing two aims. In Aim 1, we will establish the optimal conditions under which exogenous CRLF1 protects articular chondrocytes and cartilage explants in vitro when cultured under inflammatory conditions, and specifically determine whether exogenous CRLF1 as a homodimer, via promoting the internalization and degradation of the CRLF1/CLC/CNTFR complex by binding to SORLA, or both protects chondrocytes. In addition, we will determine whether the CRLF1/CLC heterodimeric complex is sufficient to induce catabolic events in chondrocytes and/or accelerates catabolic events in IL-1b-treaded chondrocytes. Using the findings obtained in Aim 1, we will determine in Aim 2 whether CRLF1 can be used in vivo to protect articular cartilage against degradation after intra-articular IL-1β injection or in a surgical-induced OA model in mice, and determine whether CRLF1/CLC complex contributes to cartilage degradation in vivo. The successful completion of this proposal will establish the role of two cytokines CRLF1 and CLC in articular cartilage homeostasis and OA pathology. We expect that the understanding of how these two cytokines individually or as a complex affect articular chondrocytes will provide novel therapeutic targets for the treatment of OA.

项目总结