Yamamoto Aiichiro, Fukuda Akira, Seto Hiroaki, Miyazaki Tsuyoshi, Kadono Yuho, Sawada Yasuhiro, Nakamura Ichiro, Katagiri Hideki, Asano Tomoichiro, Tanaka Yoshiya, Oda Hiromi, Nakamura Kozo, Tanaka Sakae
University of Tokyo, Tokyo, Japan.
Arthritis Rheum. 2003 Sep;48(9):2682-92. doi: 10.1002/art.11214.
To determine the role of Ras-mediated signaling pathways in synovial cell activation and bone destruction in arthritic joints.
The E11 rheumatoid synovial cell line and primary synovial fibroblast-like cells (SFCs) from patients with rheumatoid arthritis (RA) were gene-transferred by replication-deficient adenovirus vector carrying the dominant-negative mutant of the ras gene (AxRasDN). The effects of RasDN overexpression on cellular proliferation, interleukin-1 (IL-1)-induced activation of mitogen-activated protein kinases (extracellular signal-regulated kinase [ERK], p38, c-Jun N-terminal kinase [JNK]), and IL-6 production by synovial cells were analyzed. The in vivo effects of Ras inhibition on synovial cell activation and arthritic bone destruction were analyzed by injection of AxRasDN into ankle joints of rats with adjuvant arthritis.
AxRasDN markedly reduced the proliferation of RA SFCs. IL-1, a proinflammatory cytokine involved in RA pathology, induced activation of ERK, p38, and JNK in the cells. Adenovirus vector-mediated RasDN overexpression suppressed ERK activation, but not p38 or JNK activation, in SFCs. IL-6 is also an important proinflammatory cytokine, and RasDN inhibited IL-1-induced production of IL-6 by RA SFCs at both the transcriptional and protein levels. Injection of AxRasDN into ankle joints of rats with adjuvant arthritis ameliorated inflammation and suppressed bone destruction in the affected joints.
Ras-mediated signaling pathways are involved in the activation of RA SFCs and the destruction of bone in arthritic joints, suggesting that inhibition of Ras signaling can be a novel approach for RA treatment that targets both synovial cell activation and bone destruction in the RA joint.
确定Ras介导的信号通路在关节炎关节滑膜细胞活化和骨质破坏中的作用。
用携带ras基因显性负性突变体的复制缺陷型腺病毒载体（AxRasDN）对E11类风湿性滑膜细胞系和类风湿性关节炎（RA）患者的原代滑膜成纤维样细胞（SFCs）进行基因转移。分析RasDN过表达对细胞增殖、白细胞介素-1（IL-1）诱导的丝裂原活化蛋白激酶（细胞外信号调节激酶[ERK]、p38、c-Jun氨基末端激酶[JNK]）活化以及滑膜细胞IL-6产生的影响。通过将AxRasDN注射到佐剂性关节炎大鼠的踝关节中，分析Ras抑制对滑膜细胞活化和关节炎性骨质破坏的体内影响。
AxRasDN显著降低RA SFCs的增殖。IL-1是一种参与RA病理过程的促炎细胞因子，可诱导细胞中ERK、p38和JNK的活化。腺病毒载体介导的RasDN过表达抑制了SFCs中ERK的活化，但不抑制p38或JNK的活化。IL-6也是一种重要的促炎细胞因子，RasDN在转录和蛋白质水平上均抑制IL-1诱导的RA SFCs产生IL-6。将AxRasDN注射到佐剂性关节炎大鼠的踝关节中可改善炎症并抑制受累关节的骨质破坏。
Ras介导的信号通路参与RA SFCs的活化和关节炎关节的骨质破坏，这表明抑制Ras信号传导可能是一种针对RA关节滑膜细胞活化和骨质破坏的新型RA治疗方法。
