The Role of gp130 Cytokines in Osteoarthritis

gp130 细胞因子在骨关节炎中的作用

• 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
• 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

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 目前还没有可以阻止或减缓骨性关节炎(OA)进展的治疗方法。因此， 发现新的机制或因素，保护关节软骨细胞免受分解代谢事件和 最终减缓骨性关节炎进展过程中的软骨退化是非常必要的。最近，细胞因子 受体样因子1(CLRF1)和心肌营养素样细胞因子(CLC)是属于IL-6或 Gp130细胞因子超家族，因其潜在的潜在功能而成为研究热点。 成体生物学中的活动，在广泛的器官系统中的退化和再生条件。CRLF1 可以单独作为同源二聚体或作为异二聚体复合体与CLC一起发出信号。更重要的是，CRLF1 同源二聚体信号已被证明可以保护神经元免受氧化应激的伤害，而CRLF1/ClC 异源二聚体信号在各种组织的成体病理中发挥着重要作用。上一首 研究表明，CRLF1在骨和软骨细胞中表达。然而，人们对此知之甚少。 关于这两种细胞因子在软骨内稳态和骨关节炎病理中的作用。我们激动人心的预赛 结果显示CRLF1在骨性关节炎早期表达增加，CLC在骨性关节炎中的诱导表达 炎症条件下关节软骨细胞对人体关节分解代谢事件的刺激作用 CRLF1/ClC复合体对软骨细胞的作用，以及CRLF1单独的软骨保护作用支持我们的 假设CRLF1和CLC在软骨内稳态和骨关节炎病理中起重要作用。具体来说， 我们认为，当异二聚体CRLF1/ClC复合体刺激关节的分解代谢事件时 软骨细胞，外源性CRLF1尽管存在CLC，但在炎症中保护软骨细胞 环境。为了验证我们的假设，我们提出了两个目标。在目标1中，我们将建立最优 外源性CRLF1体外保护关节软骨细胞和软骨移植的条件 在炎症条件下培养，并特异性地确定外源CRLF1是否作为一种 同源二聚体，通过结合促进CRLF1/ClC/CNTFR复合体的内化和降解 对Sorla或两者都有保护软骨细胞的作用。此外，我们将确定CRLF1/CLC是否 异二聚体复合体足以在软骨细胞中诱导分解代谢事件和/或加速分解代谢 IL-1b作用的软骨细胞中的事件。使用在目标1中获得的结果，我们将在目标2中确定 关节内注射IL-1β后CRLF1能否在体内保护关节软骨的降解 注射或在手术诱导的小鼠骨关节炎模型中，并确定CRLF1/ClC复合体是否起作用 体内软骨的降解。这项提案的成功完成将确立两个角色 细胞因子CRLF1和ClC在关节软骨动态平衡和骨关节炎病理中的作用我们预计， 了解这两种细胞因子单独或联合如何影响关节软骨细胞 为骨性关节炎的治疗提供新的治疗靶点。