Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Department of Hand Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China.
Sci Rep. 2016 Oct 4;6:34643. doi: 10.1038/srep34643.
Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-β1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy.
强直性脊柱炎（AS）是一种慢性中轴型脊柱关节炎（SpA），可导致背痛和进行性脊柱强直。目前，由于发病机制难以捉摸，针对 AS 的有效治疗方法并不多，尽管已经确定了潜在的候选物，如 HLA-B27 自身抗原。在此，我们使用蛋白聚糖（PG）诱导的 AS 小鼠模型以及临床标本，发现补体系统在脊柱骨髓中被显著激活，同时伴有骨髓和脾脏中中性粒细胞和巨噬细胞比例的显著改变，以及血清中 TGF-β1 的显著增加。用一种来源于细菌的补体抑制剂 Efb-C（金黄色葡萄球菌细胞外纤维蛋白原结合蛋白的 C 末端）联合治疗可通过减少成骨细胞分化显著延缓小鼠 AS 的进展。此外，我们证明，在成骨细胞和/或破骨细胞中体外补体攻击可使两种参与 AS 疾病的重要调节剂 TGF-β1 和 RANKL 升高。这些发现进一步揭示了补体激活与 AS 的发病机制密切相关，并表明补体抑制可能为 AS 治疗提供巨大潜力。
