Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Department of Pathology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Inflammopharmacology. 2019 Dec;27(6):1217-1227. doi: 10.1007/s10787-019-00593-6. Epub 2019 Apr 29.
Mitogen-activated protein kinase (MAPK) signaling plays an important role in inflammatory diseases such as rheumatoid arthritis (RA).The aim of our study was to elucidate the therapeutic potential of the highly selective p38 MAPK inhibitor Skepinone-L and the dual inhibitor LN 950 (p38 MAPK and JNK 3) in the K/BxN serum transfer model of RA. Additionally, we aimed to monitor MAPK treatment non-invasively in vivo using the hypoxia tracer [F]fluoromisonidazole ([F]FMISO) and positron emission tomography (PET).
To induce experimental arthritis, we injected glucose-6-phosphate isomerase autoantibody-containing serum in BALB/c mice. MAPK inhibitor or Sham treatment was administered per os once daily. On days 3 and 6 after arthritis induction, we conducted PET imaging with [F]FMISO. At the end of the experiment, ankles were harvested for histopathological analysis.
Skepinone-L and LN 950 were applicable to suppress the severity of experimental arthritis confirmed by reduced ankle swelling and histopathological analysis. Skepinone-L (3.18 ± 0.19 mm) and LN 950 (3.40 ± 0.13 mm) treatment yielded a significantly reduced ankle thickness compared to Sham-treated mice (3.62 ± 0.11 mm) on day 5 after autoantibody transfer, a time-point characterized by severe arthritis. Hypoxia imaging with [F]FMISO revealed non-conclusive results and might not be an appropriate tool to monitor MAPK therapy in experimental RA.
Both the selective p38 MAPK inhibitor Skepinone-L and the dual (p38 MAPK and JNK 3) inhibitor LN 950 exhibited significant therapeutic effects during experimental arthritis. Thus, our study contributes to the ongoing discussion on the use of p38 MAPK as a potential target in RA.
丝裂原活化蛋白激酶（MAPK）信号通路在类风湿关节炎（RA）等炎症性疾病中发挥着重要作用。本研究旨在阐明高度选择性 p38 MAPK 抑制剂 Skepinone-L 和双重抑制剂 LN 950（p38 MAPK 和 JNK 3）在 K/BxN 血清转移型 RA 模型中的治疗潜力。此外，我们旨在通过缺氧示踪剂 [F]氟米索硝唑（[F]FMISO）和正电子发射断层扫描（PET）对 MAPK 治疗进行非侵入性体内监测。
为了诱导实验性关节炎，我们向 BALB/c 小鼠注射含有葡萄糖-6-磷酸异构酶自身抗体的血清。MAPK 抑制剂或假处理通过口服每天一次进行。在关节炎诱导后第 3 和第 6 天，我们进行了 [F]FMISO 的 PET 成像。在实验结束时，采集踝关节进行组织病理学分析。
Skepinone-L 和 LN 950 可用于抑制实验性关节炎的严重程度，这通过减轻踝关节肿胀和组织病理学分析得到证实。Skepinone-L（3.18±0.19mm）和 LN 950（3.40±0.13mm）治疗与 Sham 治疗的小鼠相比，在自身抗体转移后第 5 天踝关节厚度显著降低，这是关节炎严重的时间点。[F]FMISO 的缺氧成像结果并不一致，可能不是监测实验性 RA 中 MAPK 治疗的合适工具。
选择性 p38 MAPK 抑制剂 Skepinone-L 和双重（p38 MAPK 和 JNK 3）抑制剂 LN 950 在实验性关节炎中均表现出显著的治疗效果。因此，我们的研究为 p38 MAPK 作为 RA 潜在靶点的应用提供了依据。
