Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Sweden.
J Leukoc Biol. 2011 Oct;90(4):811-7. doi: 10.1189/jlb.1110640. Epub 2011 Jul 19.
TKs are intracellular signaling molecules essential for cell homeostasis. Inhibition of TKs is used in treatment of malignancies and diabetes mellitus. The present study evaluated the role of Flt3 in antigen-induced arthritis. Mice were immunized with mBSA, and arthritis was induced by an i.a. injection of mBSA. Treatment with the Flt3 inhibitor sunitinib was started together with mBSA immunization or together with the induction of arthritis. The mBSA-injected joints were evaluated morphologically for signs of synovitis and bone/cartilage destruction. Markers of bone metabolism and antibody responses were measured by ELISA. Maturation of DCs in the bone marrow and spleen was evaluated by flow cytometry. Sunitinib treatment reduced the intensity of synovitis and the incidence of bone destruction. The reduction in bone destruction was seen when the treatment was started at the time of immunization or at the time of arthritis induction. The antiarthritic effect was achieved by inhibition of DCs, reduction of antibody production, and bone metabolism. Inhibition of Flt3 is a potent antiarthritic mechanism reducing antigen presentation, synovial inflammation, and bone resorption. Down-regulation of TKs may be a useful tool in the treatment of human RA.
TKs 是细胞内信号分子，对细胞内稳态至关重要。TKs 的抑制被用于治疗恶性肿瘤和糖尿病。本研究评估了 Flt3 在抗原诱导性关节炎中的作用。用 mBSA 免疫小鼠，通过关节内注射 mBSA 诱导关节炎。Flt3 抑制剂舒尼替尼的治疗与 mBSA 免疫或关节炎诱导同时开始。用形态学方法评估注射 mBSA 的关节，以评估滑膜炎和骨/软骨破坏的迹象。通过 ELISA 测量骨代谢和抗体反应的标志物。通过流式细胞术评估骨髓和脾脏中 DC 的成熟。舒尼替尼治疗减轻了滑膜炎的强度和骨破坏的发生率。当治疗在免疫或关节炎诱导时开始时，观察到骨破坏的减少。抗关节炎作用是通过抑制 DC、减少抗体产生和骨代谢来实现的。抑制 Flt3 是一种有效的抗关节炎机制，可减少抗原呈递、滑膜炎症和骨吸收。下调 TK 可能是治疗人类 RA 的有用工具。
