CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.
Front Immunol. 2018 Nov 14;9:2641. doi: 10.3389/fimmu.2018.02641. eCollection 2018.
Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis. Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation. Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling. The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.
尽管进行了广泛的研究，但脊柱关节炎（尤其是强直性脊柱炎）的确切发病机制仍难以捉摸。本研究旨在建立理想的动物模型，深入了解脊柱关节炎的发病机制以及 SOCS3 在脊柱关节炎中的功能相关性。由于 SOCS3 是 IL23-STAT3 信号的主要调节因子，我们构建了 SOCS3 敲低转基因（TG）小鼠，以建立脊柱关节炎的动物模型。采用流体动力学递送方法将表达 IL23 的微小环 DNA（mc-IL23）递送至野生型（WT）和 TG 小鼠。使用慢病毒和逆转录病毒介导的敲低/过表达系统来确定 SOCS3 是否调节成骨细胞分化。强制表达 IL23 可诱导 SOCS3 敲低 TG 小鼠发生严重的关节破坏和广泛的骨质流失，而在 WT 小鼠中仅引起中度症状。此外，与 WT 对照组相比，在相同条件下，IL23 注射的 TG 小鼠中出现严重的脊柱关节炎，而 WT 对照组中仅观察到轻度疾病。此外，我们的研究表明，IL23 通过激活 STAT3 通路促进成骨细胞分化，并且破坏 SOCS3 表达会极大地增加 STAT3 的磷酸化。此外，沉默 SOCS3 通过激活 Smad1/5/9 信号通路促进成骨细胞分化，这表现为 Smad1/5/9 的磷酸化水平升高。实验进一步表明，SOCS3 与 Smad1 相互作用，从而抑制 BMP2-Smad 信号通路。研究结果表明，SOCS3 参与了 IL23 诱导的脊柱关节炎，并且是成骨细胞分化的关键调节因子，提示 SOCS3 敲低 TG 小鼠可能是进一步研究脊柱关节炎的理想动物模型。
