The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Impact Biotech, Seoul, South Korea.
Front Immunol. 2018 Dec 11;9:2881. doi: 10.3389/fimmu.2018.02881. eCollection 2018.
Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation. Signal transducer and activator of transcription 3 (STAT3) modulates secretion of many proinflammatory cytokines. Experimental OA was induced by intra-articular (IA) injection of monosodium iodoacetate (MIA) to the right knee of rats. MSCs from OA patients (OA-MSCs) were treated with STA21, a small molecule that blocks STAT3 signaling, by IA or intravenous (IV) injection after MIA injection. Pain severity was quantified by assessment of secondary tactile allodynia using the von Frey assessment test. Cartilage degradation was measured by microcomputed tomography image analysis, histological analysis, and the Mankin score. Protein and gene expression was evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and real-time polymerase chain reaction. MSCs increased production of proinflammatory cytokines under inflammatory conditions. STA21 significantly decreased expression of these proinflammatory molecules via inhibition of STAT3 activity but increased gene expression of molecules related to migration potential and immunomodulation in OA-MSCs. STAT3-inhibited OA-MSCs administrated by IV or IA injection decreased pain severity and cartilage damage in rats with MIA-induced OA rats by decreasing proinflammatory cytokines in the joints. Combined IA and IV-injected STAT3-inhibited OA-MSCs had an additive effect of pain relief in MIA-induced OA rats. STAT3 inhibition may optimize the therapeutic activities of MSCs for treating OA by attenuating pain and progression of MIA by inhibiting inflammation and cartilage damage.
骨关节炎（OA）是一种退行性疾病，可引起疼痛、软骨变形和关节炎症。间充质干细胞（MSCs）是治疗 OA 的潜在治疗剂。然而，MSC 治疗可能会引起过度炎症。信号转导子和转录激活子 3（STAT3）调节许多促炎细胞因子的分泌。通过向大鼠右膝关节内注射单碘乙酸盐（MIA）来诱导实验性 OA。在 MIA 注射后，通过关节内（IA）或静脉内（IV）注射，用小分子阻断 STAT3 信号的 STA21 处理来自 OA 患者的 MSC（OA-MSCs）。通过 von Frey 评估试验评估继发性触觉过敏来量化疼痛严重程度。通过微计算机断层扫描图像分析、组织学分析和 Mankin 评分测量软骨降解。通过酶联免疫吸附试验、免疫组织化学和实时聚合酶链反应评估蛋白质和基因表达。MSCs 在炎症条件下增加促炎细胞因子的产生。STA21 通过抑制 STAT3 活性显着降低这些促炎分子的表达，但增加 OA-MSCs 中与迁移潜力和免疫调节相关的分子的基因表达。通过减少关节中的促炎细胞因子，通过 IV 或 IA 注射给予的 STAT3 抑制的 OA-MSCs 减轻了 MIA 诱导的 OA 大鼠的疼痛严重程度和软骨损伤。联合 IA 和 IV 注射的 STAT3 抑制的 OA-MSCs 在 MIA 诱导的 OA 大鼠中具有缓解疼痛的附加作用。通过抑制炎症和软骨损伤，STAT3 抑制可能通过减轻疼痛和 MIA 的进展来优化 MSC 治疗 OA 的治疗活性。
