Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation.
Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation.
复制标题
瞬态受体电位规范5（TRPC5）可预防关节炎和关节炎症中的疼痛和血管炎症。
DOI：
10.1136/annrheumdis-2015-208886
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发表时间：
2017-01
影响因子：
27.4
通讯作者：
Brain SD
中科院分区：
文献类型：
--
作者：
Alawi KM;Russell FA;Aubdool AA;Srivastava S;Riffo-Vasquez Y;Baldissera L Jr;Thakore P;Saleque N;Fernandes ES;Walsh DA;Brain SD
瞬时受体电位规范 5 (TRPC5) 在包括成纤维样滑膜细胞在内的一系列细胞上功能性表达，这些细胞在关节炎中发挥重要作用。 TRPC5 在炎症中的作用此前尚未在体内得到证实。我们研究了 TRPC5 在关节炎中的作用。将雄性野生型和 TRPC5 敲除 (KO) 小鼠用于完全弗氏佐剂 (CFA) 诱导的单侧关节炎模型，评估超过 14 天。通过测量膝关节直径、后肢负重不对称性和疼痛行为来确定关节炎。单独的研究涉及 TRPC5 通道的长期药理学拮抗作用。研究了人类死后对照和炎性关节炎样本滑膜的 TRPC5 基因表达。在基线时，没有观察到差异。通过组织学评估，CFA诱导的关节炎导致TRPC5 KO小鼠滑膜炎增加。此外，TRPC5 KO 小鼠在 CFA 诱导的关节炎后表现出同侧负重和伤害感受阈值（热阈值和机械阈值）降低。这与同侧滑膜中炎症介质 mRNA 表达增加以及滑液灌洗液中细胞因子浓度增加有关。使用 TRPC5 拮抗剂 ML204 进行长期治疗，可增强负重不对称性、继发性痛觉过敏和滑液灌洗液中的细胞因子浓度。来自人类炎症性关节炎的滑液显示 TRPC5 mRNA 表达减少。 TRPC5 的基因缺失或药理学阻断会导致关节炎症和痛觉过敏的增强。我们的结果表明，TRPC5 的激活可能与炎症性关节病症中的内源性抗炎/镇痛途径有关。
Transient receptor potential canonical 5 (TRPC5) is functionally expressed on a range of cells including fibroblast-like synoviocytes, which play an important role in arthritis. A role for TRPC5 in inflammation has not been previously shown in vivo. We investigated the contribution of TRPC5 in arthritis. Male wild-type and TRPC5 knockout (KO) mice were used in a complete Freund's adjuvant (CFA)-induced unilateral arthritis model, assessed over 14 days. Arthritis was determined by measurement of knee joint diameter, hindlimb weightbearing asymmetry and pain behaviour. Separate studies involved chronic pharmacological antagonism of TRPC5 channels. Synovium from human postmortem control and inflammatory arthritis samples were investigated for TRPC5 gene expression. At baseline, no differences were observed. CFA-induced arthritis resulted in increased synovitis in TRPC5 KO mice assessed by histology. Additionally, TRPC5 KO mice demonstrated reduced ispilateral weightbearing and nociceptive thresholds (thermal and mechanical) following CFA-induced arthritis. This was associated with increased mRNA expression of inflammatory mediators in the ipsilateral synovium and increased concentration of cytokines in synovial lavage fluid. Chronic treatment with ML204, a TRPC5 antagonist, augmented weightbearing asymmetry, secondary hyperalgesia and cytokine concentrations in the synovial lavage fluid. Synovia from human inflammatory arthritis demonstrated a reduction in TRPC5 mRNA expression. Genetic deletion or pharmacological blockade of TRPC5 results in an enhancement in joint inflammation and hyperalgesia. Our results suggest that activation of TRPC5 may be associated with an endogenous anti-inflammatory/analgesic pathway in inflammatory joint conditions.