Tanaka Konagi, Horikawa Tatsuya, Suzuki Satsuki, Kitaura Kazutaka, Watanabe Junko, Gotoh Akito, Shiobara Noriyuki, Itoh Tsunetoshi, Yamane Shoji, Suzuki Ryuji, Fukui Naoshi, Ochi Takahiro
Clinical Research Center, National Hospital Organization, Sagamihara Hospital, Sagamihara, Kanagawa, Japan.
J Rheumatol. 2008 Dec;35(12):2316-24. doi: 10.3899/jrheum.080369. Epub 2008 Nov 1.
To investigate whether the blockade of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) has any therapeutic effects on rheumatoid arthritis.
A functional blocking monoclonal antibody for SHPS-1 (anti-SHPS-1 mAb) was administered at various doses to collagen-induced arthritis (CIA) mice, and severity of the arthritis was evaluated by clinical and histological scores of the limbs. To clarify the mechanisms of action of the antibody, the serum concentration of anti-type II collagen antibody was measured in those mice, and in vitro experiments were conducted to determine the effects of the antibody on the induction of osteoclasts and the release of cytokines from mouse spleen cells.
Compared with mice given control IgG, the administration of anti-SHPS-1 mAb significantly reduced the severity of inflammation and destruction of bone and cartilage in CIA mice. This therapeutic effect was observed even when the antibody treatment was started after the onset of arthritis. The appearance of anti-type II collagen antibody in CIA mice was not altered by the antibody treatment. In in vitro experiments, the anti-SHPS-1 mAb significantly inhibited osteoclastogenesis of bone marrow cells, and significantly reduced the release of interleukin 1beta (IL-1beta), IL-2, IL-12, interferon-gamma, and tumor necrosis factor-alpha, but not that of IL-4 or IL-10, from the spleen cells after stimulation with concanavalin A.
Administration of a monoclonal antibody for SHPS-1 reduced the severity of arthritis in CIA mice. Regulation of biological functions of SHPS-1 may be a novel and potent strategy to treat patients with rheumatoid arthritis.
研究Src同源2结构域含蛋白酪氨酸磷酸酶底物-1（SHPS-1）的阻断是否对类风湿关节炎有治疗作用。
将不同剂量的SHPS-1功能性阻断单克隆抗体（抗SHPS-1单克隆抗体）给予胶原诱导性关节炎（CIA）小鼠，并通过四肢的临床和组织学评分评估关节炎的严重程度。为阐明该抗体的作用机制，测定了这些小鼠血清中抗II型胶原抗体的浓度，并进行体外实验以确定该抗体对破骨细胞诱导及小鼠脾细胞细胞因子释放的影响。
与给予对照IgG的小鼠相比，抗SHPS-1单克隆抗体的给药显著降低了CIA小鼠炎症的严重程度以及骨和软骨的破坏。即使在关节炎发病后开始抗体治疗，也观察到了这种治疗效果。抗体治疗未改变CIA小鼠中抗II型胶原抗体的出现情况。在体外实验中，抗SHPS-1单克隆抗体显著抑制骨髓细胞的破骨细胞生成，并显著降低用伴刀豆球蛋白A刺激后脾细胞中白细胞介素1β（IL-1β）、IL-2、IL-12、干扰素-γ和肿瘤坏死因子-α的释放，但不影响IL-4或IL-10的释放。
给予SHPS-1单克隆抗体可降低CIA小鼠关节炎的严重程度。调节SHPS-1的生物学功能可能是治疗类风湿关节炎患者的一种新的有效策略。
