Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice
Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice
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DOI：
10.1073/pnas.052523599
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发表时间：
2002-04-02
影响因子：
11.1
通讯作者：
Noda, M
中科院分区：
文献类型：
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作者：
Yumoto, K;Ishijima, M;Noda, M
类风湿关节炎是影响患者生活质量的重要疾病之一，但其发病机制尚不完全清楚。骨桥蛋白（OPN）是一种含有arg - gy - asp （RGD）序列的细胞外基质蛋白，与α - β 3整合素相互作用，促进细胞附着和细胞迁移，并在类风湿关节炎的滑膜细胞和软骨细胞中表达；然而，其与关节炎的功能关系尚不清楚。因此，我们研究了OPN在抗II型胶原单抗和脂多糖（mab /LPS）混合诱导的类风湿关节炎模型炎症过程中的作用。单抗/LPS注射诱导滑膜和软骨中OPN的表达，这种表达与野生型小鼠关节肿胀、关节表面结构破坏以及关节软骨中甲苯胺蓝阳性蛋白聚糖含量的减少有关。相比之下，OPN缺乏使小鼠即使在单克隆抗体作用下也不会出现这种表面破坏、关节软骨蛋白聚糖的丧失和关节肿胀，，。嘴唇注射。此外，在野生型小鼠中注射单克隆抗体/LPS可提高滑膜中cd31阳性血管和末端脱氧核苷酸转移酶介导的UTP末端标记阳性软骨细胞的水平，而在opn缺陷小鼠中，这种血管生成和软骨细胞凋亡被显著抑制。这些结果表明，OPN通过促进血管生成和诱导软骨细胞凋亡，在类风湿性关节炎模型小鼠关节软骨的破坏中起关键作用。
Rheumatoid arthritis is one of the most critical diseases that impair the quality of life of patients, but its pathogenesis has not yet been fully understood. Osteopontin (OPN) is an extracellular matrix protein containing Arg-Gly-Asp (RGD) sequence, which interacts with alphanubeta3 integrins, promotes cell attachment, and cell migration and is expressed in both synovial cells and chondrocytes in rheumatoid arthritis; however, its functional relationship to arthritis has not been known. Therefore, we investigated the roles of OPN in the pathogenesis of inflammatory process in a rheumatoid arthritis model induced by a mixture of anti-type II collagen mAbs and lipopolysaccharide (mAbs/LPS). mAbs/LPS injection induced OPN expression in synovia as well as cartilage, and this expression was associated with joint swelling, destruction of the surface structures of the joint based on scanning electron microscopy, and loss of toluidine blue-positive proteoglycan content in the articular cartilage in wild-type mice. In contrast, OPN deficiency prevented the mice from such surface destruction, loss of proteoglycan in the articular joint cartilage, and swelling of the joints even when the mice were subjected to mAbs,,. LIPS injection. Furthermore, mAbs/LPS injection in wild-type mice enhanced the levels of CD31-positive vessels in synovia and terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive chondrocytes in the articular cartilage, whereas such angiogenesis as well as chondrocyte apoptosis was suppressed significantly in OPN-deficient mice. These results indicated that OPN plays a critical role in the destruction of joint cartilage in the rheumatoid arthritis model in mice via promotion of angiogenesis and induction of chondrocyte apoptosis.