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.

项目概要 目前尚无有效的治疗方法可以阻止或减缓骨关节炎 (OA) 的进展。所以， 发现保护关节软骨细胞免受分解代谢事件的新机制或因素，以及 迫切需要最终减缓 OA 进展过程中的软骨退化。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)，这两种细胞因子属于 IL-6 或 gp130 细胞因子超家族因其潜力而成为深入研究的对象 成人生物学活动、多种器官系统的退化和再生条件。回车换行1 可以作为同二聚体或作为与 CLC 一起的异二聚体复合物单独发出信号。更重要的是，CRLF1 同二聚体信号传导已被证明可以保护神经元免受氧化应激，而 CRLF1/CLC 异二聚体信号传导已被证明在各种组织的成人病理学中发挥重要作用。以前的 研究表明 CRLF1 由骨和软骨细胞表达。然而，人们所知甚少 关于这两种细胞因子在软骨稳态和 OA 病理学中的作用。我们激动人心的预赛 研究结果显示，在 OA 早期阶段 CRLF1 表达增加，诱导 CLC 表达 炎症条件下的关节软骨细胞，刺激人体关节的分解代谢事件 CRLF1/CLC 复合物对软骨细胞的保护作用，单独 CRLF1 的软骨保护作用支持了我们的研究 假设 CRLF1 和 CLC 在软骨稳态和 OA 病理学中发挥重要作用。具体来说， 我们认为，虽然异二聚体 CRLF1/CLC 复合物刺激关节内的分解代谢事件，但 软骨细胞，尽管存在 CLC，外源性 CRLF1 仍可保护炎症中的软骨细胞 环境。为了检验我们的假设，我们提出两个目标。在目标 1 中，我们将建立最优 外源 CRLF1 在体外保护关节软骨细胞和软骨外植体的条件 在炎症条件下培养，并特异性确定外源CRLF1是否作为 同二聚体，通过结合促进 CRLF1/CLC/CNTFR 复合物的内化和降解 SORLA 或两者都保护软骨细胞。另外，我们还会判断CRLF1/CLC是否 异二聚体复合物足以诱导软骨细胞中的分解代谢事件和/或加速分解代谢 IL-1b 处理的软骨细胞中的事件。利用目标 1 中获得的结果，我们将确定目标 2 CRLF1是否可以在体内用于关节内IL-1β后保护关节软骨免遭降解 注射或手术诱导的小鼠 OA 模型，并确定 CRLF1/CLC 复合物是否有助于 导致体内软骨退化。该提案的成功完成将确立两个角色的作用： 细胞因子 CRLF1 和 CLC 在关节软骨稳态和 OA 病理学中的作用。我们期望 了解这两种细胞因子单独或作为复合物如何影响关节软骨细胞 为OA的治疗提供新的治疗靶点。