Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts
Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts
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DOI：
10.1172/jci6093
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发表时间：
1999-07-01
影响因子：
15.9
通讯作者：
Tanaka, S
中科院分区：
文献类型：
--
作者：
Takayanagi, H;Juji, T;Tanaka, S
类风湿性关节炎（RA）的特点是滑膜关节的慢性炎症，由滑膜成纤维细胞增生和淋巴细胞、巨噬细胞和浆细胞的浸润引起，其中所有细胞都表现出活化的迹象。近年来的研究揭示了破骨细胞在类风湿关节炎关节破坏中的重要作用。Src家族酪氨酸激酶参与多种细胞内信号通路，包括成纤维细胞对生长因子的有丝分裂反应、淋巴细胞的激活和破骨细胞骨吸收。因此，抑制Src活性可能是预防RA关节炎症和破坏的良好治疗策略。我们构建了一个携带csk基因的腺病毒载体，该基因负调控Src家族酪氨酸激酶。在培养的类风湿性滑膜细胞中，ssk过表达可显著抑制Src激酶活性，降低其增殖率和IL-6的产生。破骨细胞的骨吸收活性受Csk过表达的强烈抑制。此外，在佐剂性关节炎大鼠踝关节局部注射病毒不仅能改善炎症，还能抑制骨破坏。总之，腺病毒介导的csk基因的直接转移在抑制骨破坏和炎症反应中是有用的，这表明Src家族酪氨酸激酶参与关节炎关节破裂，并证明了干预这些激酶进行RA基因治疗的可行性。
Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and infiltration of lymphocytes, macrophages, and plasma cells, arl of which manifest signs of activation. Recent studies have revealed the essential role of osteoclasts in joint destruction in RA. Src family tyrosine kinases are implicated in various intracellular signaling pathways, including mitogenic response to growth factors in fibroblasts, activation of lymphocytes, and osteoclastic bone resorption. Therefore, inhibiting Src activity can be a good therapeutic strategy to prevent joint inflammation and destruction in RA. We constructed an adenovirus vector carrying the csk gene, which negatively regulates Src family tyrosine kinases. Csk overexpression in cultured rheumatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production. Bone-resorbing activity of osteoclasts tvas strongly inhibited by Csk overexpression. Furthermore, local injection of the virus into rat ankle joints with adjuvant arthritis not only ameliorated inflammation but suppressed bone destruction. In conclusion, adenovirus-mediated direct transfer of the csk gene is useful in repressing bone destruction and inflammatory reactions, suggesting the involvement of Src family tyrosine kinases in arthritic joint breakdown and demonstrating the feasibility of intervention in the kinases for gene therapy in RA.