Rheumatoid arthritis is frequently associated with chronic pain that still remains difficult to treat. Targeting nerve growth factor (NGF) seems very effective to reduce pain in at least, osteoarthritis and chronic low back pain but leads to some potential adverse events. Our aim was to better understand the involvement of the intracellular signalling pathways activated by NGF through its specific tyrosine kinase type A (TrkA) receptor in the pathophysiology of rheumatoid arthritis using the complete Freund adjuvant model in our knock-in TrkA/C mice. Our multimodal study demonstrated that knock-in TrkA/C mice exhibited a specific decrease of mechanical allodynia, weight bearing deficit, peptidergic (CGRP+) and sympathetic (TH+) peripheral nerve sprouting in the joints, a reduction in osteoclast activity and bone resorption markers, and a decrease of CD68 positive cells in the joint with no apparent changes in joint inflammation compared to WT mice following arthritis. Finally, transcriptomic analysis show several differences in DRGs mRNA expression of putative mechanotransducers such as ASIC3 and TRAAK as well as intracellular pathways such as c-Jun in the joint/DRGs. These results suggest that TrkA specific intracellular signalling pathways are specifically involved in mechanical hypersensitivity and bone alterations following arthritis using TrkA/C mice.

中文翻译：

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TrkA 特异性信号通路对于类风湿性关节炎小鼠模型中的机械异常性疼痛发展和骨骼改变至关重要。

类风湿性关节炎经常与仍然难以治疗的慢性疼痛有关。靶向神经生长因子 (NGF) 似乎对减轻骨关节炎和慢性腰痛的疼痛非常有效，但会导致一些潜在的不良事件。我们的目的是在我们的敲入 TrkA/C 小鼠中使用完整的弗氏佐剂模型，更好地了解 NGF 通过其特异性酪氨酸激酶 A 型 (TrkA) 受体激活的细胞内信号通路参与类风湿性关节炎的病理生理学。我们的多模式研究表明，敲入 TrkA/C 小鼠的机械异常性疼痛、负重不足、关节中肽能 (CGRP+) 和交感 (TH+) 周围神经的发芽、破骨细胞活性和骨吸收标志物的减少，与关节炎后的WT小鼠相比，关节中CD68阳性细胞减少，关节炎症没有明显变化。最后，转录组学分析显示了推定的机械传感器（如 ASIC3 和 TRAAK）的 DRGs mRNA 表达以及关节/DRGs 中的 c-Jun 等细胞内途径的几个差异。这些结果表明，使用 TrkA/C 小鼠，TrkA 特异性细胞内信号通路特别参与了关节炎后的机械超敏反应和骨改变。转录组学分析显示推定的机械传感器（如 ASIC3 和 TRAAK）的 DRGs mRNA 表达以及关节/DRGs 中的 c-Jun 等细胞内途径存在若干差异。这些结果表明，使用 TrkA/C 小鼠，TrkA 特异性细胞内信号通路特别参与了关节炎后的机械超敏反应和骨改变。转录组学分析显示推定的机械传感器（如 ASIC3 和 TRAAK）的 DRGs mRNA 表达以及关节/DRGs 中的 c-Jun 等细胞内途径存在若干差异。这些结果表明，使用 TrkA/C 小鼠，TrkA 特异性细胞内信号通路特别参与了关节炎后的机械超敏反应和骨改变。