Bone and Cartilage Research Unit, Arthropôle Liège, University of Liège, Institute of Pathology, CHU Sart-Tilman, 4000, Liège, Belgium.
INSERM UMR 1124, Laboratory of Pharmacology, Toxicology and Cell Signaling, University Paris-Descartes, Paris, France; Department of Automated Biological Diagnostic, Cochin Hospital, APHP, University Paris Descartes, Paris, France.
Osteoarthritis Cartilage. 2019 Nov;27(11):1680-1691. doi: 10.1016/j.joca.2019.07.009. Epub 2019 Jul 17.
We evaluated the ability of Coll2-1, a type II collagen peptide, to activate pro-inflammatory pathways in synovial cells and to induce arthritis in Lewis rats.
Human synoviocytes and chondrocytes from knee OA patients were cultured for 24 h with/without Coll2-1 and/or purified immunoglobulin G (AS0619) binding specifically this peptide, and/or CLI-095, a TLR-4 signaling inhibitor and/or apocynin and diphenyleneiodonium, Reactive oxygen species (ROS) production inhibitors. The Interleukin (IL)-8 and Vascular Endothelium Growth Factor (VEGF) expression, the IL-8 production, the IκB-α and p65 phosphorylation and ROS were evaluated. Coll2-1 peptide, bovine type II collagen (CIA), streptococcal cell wall (SCW) or saline solution were injected into Lewis rats. The Coll2-1 peptide was injected subcutaneously (SC; 20-200μg/100μl/animal) or intra-articularly (IA; 0.5-5μg/50μl/animal) and compared to CIA injected in SC (200μg/100μl/animal) and SCW in IA (5μg/50μl/animal). The animals were injected on day 0 and monitored for 28 days. Histological lesions assessment was performed using an arthritis score.
Coll2-1 peptide significantly increased IL-8 gene expression and production by synoviocytes. AS0619 and CLI-095 significantly decreased IL-8 expression. Coll2-1 induced p65 and IκBα phosphorylation and oxidative stress inhibitors decreased it. In human chondrocytes culture, Coll2-1 significantly increased MMP-3 and VEGF gene expression. In Lewis rats, CIA, SCW or Coll2-1 injection triggered arthritis. Like CIA or SCW, Coll2-1 induced synovitis, loss of cartilage proteoglycans, cartilage structure lesion and subchondral bone remodeling.
Coll2-1 activates synoviocytes to produce IL-8 and induces arthritis in rat. These findings suggest that neutralizing Coll2-1 could be a therapeutic approach of arthritis.
评估 II 型胶原肽 Coll2-1 激活滑膜细胞促炎途径并在 Lewis 大鼠中诱导关节炎的能力。
用 Coll2-1 和/或特异性结合该肽的纯化免疫球蛋白 G（AS0619）以及 TLR-4 信号抑制剂 CLI-095 和活性氧（ROS）产生抑制剂 apocynin 和二苯基碘二铵处理来自膝骨关节炎患者的人滑膜细胞和软骨细胞 24 小时，并检测白细胞介素（IL）-8 和血管内皮生长因子（VEGF）的表达、IL-8 的产生、IκB-α 和 p65 的磷酸化以及 ROS。Coll2-1 肽、牛 II 型胶原（CIA）、链球菌细胞壁（SCW）或生理盐水溶液被注射到 Lewis 大鼠中。Coll2-1 肽被皮下（SC；20-200μg/100μl/动物）或关节内（IA；0.5-5μg/50μl/动物）注射，并与 CIA 皮下注射（200μg/100μl/动物）和 SCW 关节内注射（5μg/50μl/动物）进行比较。动物在第 0 天注射，并监测 28 天。使用关节炎评分对组织学病变进行评估。
Coll2-1 肽显著增加滑膜细胞中 IL-8 的基因表达和产生。AS0619 和 CLI-095 显著降低了 IL-8 的表达。Coll2-1 诱导 p65 和 IκBα 的磷酸化，而 ROS 抑制剂则降低了其磷酸化。在人软骨细胞培养中，Coll2-1 显著增加 MMP-3 和 VEGF 的基因表达。在 Lewis 大鼠中，CIA、SCW 或 Coll2-1 注射引发关节炎。与 CIA 或 SCW 一样，Coll2-1 诱导滑膜炎、软骨蛋白聚糖丧失、软骨结构损伤和软骨下骨重塑。
Coll2-1 激活滑膜细胞产生 IL-8，并在大鼠中诱导关节炎。这些发现表明，中和 Coll2-1 可能是关节炎的一种治疗方法。
