Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
Department of Parasitology and Tropical Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
Rheumatology (Oxford). 2021 Aug 2;60(8):3923-3935. doi: 10.1093/rheumatology/keaa846.
AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 phosphorylation inhibitor (stat3-p Inh) could treat both chronic inflammation and bone formation in AS.
Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p Inh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT.
In the SKG mouse model, stat3-p Inh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-γ-, IL-17A- and TNF-α-producing cells were significantly decreased after stat3-p Inh treatment. When comparing current treatments for AS, stat3-p Inh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p Inh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p Inh-treated mice than vehicle-treated mice (P = 0.005). Hind paw and spinal new bone formation were similar between stat3-p Inh- and anti-IL-17A-treated SKG mice (P = 0.874 and P = 0.117, respectively).
Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.
强直性脊柱炎（AS）是一种以慢性炎症和骨强直为特征的风湿病。本研究旨在评估信号转导子和转录激活子 3 磷酸化抑制剂（stat3-pInh）是否能同时治疗 AS 的慢性炎症和骨形成。
检测原发性 AS 成骨前体细胞和脊柱附着细胞的成骨分化情况。从 AS 患者中获得滑膜单核细胞（SFMCs）和固有层单核细胞（LPMCs）。采用流式细胞术和 ELISA 分析产生炎性细胞因子的细胞。用 stat3-pInh、IL-17A 阻断剂或载体治疗雌性 SKG 小鼠。采用免疫组织化学、PET 和 micro-CT 评估炎症和新骨形成。
在 SKG 小鼠模型中，stat3-pInh 显著抑制关节炎、附着点炎、脊柱炎和回肠炎。在 SFMCs 和 LPMCs 的培养实验中，stat3-pInh 处理后 IFN-γ、IL-17A 和 TNF-α 产生细胞的频率显著降低。与 AS 的当前治疗方法相比，stat3-pInh 对 AS 成骨前体细胞的成骨作用的抑制作用与 Janus 激酶抑制剂或 IL-17A 阻断剂相当。Stat3-pInh 抑制 AS 成骨前体细胞和附着细胞向成骨细胞的分化和矿化。后爪 micro-CT 分析显示，stat3-pInh 治疗组比载体治疗组的新骨形成减少（P=0.005）。Stat3-pInh 治疗组和抗 IL-17A 治疗组的后爪和脊柱新骨形成相似（P=0.874 和 P=0.117）。
Stat-3p 抑制是治疗 AS 中炎症和新骨形成的一种有前途的方法。
