Hyaluronan Inhibits Matrix Metalloproteinase-13 in Human Arthritic Chondrocytes via CD44 and P38
Hyaluronan Inhibits Matrix Metalloproteinase-13 in Human Arthritic Chondrocytes via CD44 and P38
复制标题
DOI：
10.1002/jor.21216
复制
发表时间：
2011-02-01
影响因子：
2.8
通讯作者：
Nakamura, Takashi
中科院分区：
文献类型：
--
作者：
Julovi, Sohel M.;Ito, Hiromu;Nakamura, Takashi
我们研究了透明质酸 (HA) 对骨关节炎 (OA) 或类风湿性关节炎 (RA) 患者软骨细胞中白细胞介素 1 β (IL-1 β) 刺激的基质金属蛋白酶 (MMP)-13 产生的影响。通过免疫印迹检测条件培养基中MMP-13的分泌水平，同时通过免疫荧光显微镜分析评估关节软骨中细胞内MMP-13的合成。通过蛋白质印迹法评估丝裂原激活蛋白激酶 (MAPK)、p38、细胞外信号调节激酶 (ERK) 和 c-jun NH2 末端激酶 (JNK)。 IL-1 beta (2 ng/ml) 刺激 OA 和 RA 软骨细胞分泌 MMP-13。使用特定 MAPK 抑制剂的抑制研究表明，IL-1 beta 在 OA 和 RA 软骨细胞中通过 p38 诱导 MMP-13。 HA 以剂量依赖性方式（0.1、1、2 和 4 mg/ml）下调 IL-1 β 刺激的 MMP-13 和磷酸化 p38 (p-p38)。当使用 4 mg/ml 时，HA 可抑制 p-p38 磷酸化超过 60%。响应 IL-1 beta，RA 软骨细胞比 OA 软骨细胞表达更高水平的 p-p38。使用封闭抗体抑制 CD44 可显着逆转 HA 对 MMP-13 和 p-p38 的抑制作用。我们的研究清楚地表明，HA 通过其主要受体 CD44 以及随后 OA 和 RA 软骨细胞中的细胞内 p38 MAPK 信号传导抑制 IL-1 β 诱导的 MMP-13。 (C) 2010 年骨科研究学会。由 Wiley periodicals, Inc. J. Orthop 出版。资源。 29：258-264，2011
We investigated the effects of hyaluronan (HA) on interleukin-1 beta (IL-1 beta)-stimulated matrix metalloproteinase (MMP)-13 production in human chondrocytes from patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Secreted levels of MMP-13 in conditioned media were detected by immunoblotting, while intracellular MMP-13 synthesis in articular cartilage was evaluated by immunofluorescence microscopic analysis. Mitogen-activated protein kinases (MAPKs), p38, extracellular signal-regulated kinases (ERK), and c-jun NH2-terminal kinase (JNK) were assessed by Western blotting. IL-1 beta (2 ng/ml) stimulates the secretion of MMP-13 in both OA and RA chondrocytes. Inhibition studies using specific MAPK inhibitors revealed that IL-1 beta induced MMP-13 via p38 in both OA and RA chondrocytes. HA down-regulates IL-1 beta-stimulated MMP-13 and phosphorylated p38 (p-p38) in a dose-dependent manner (0.1, 1, 2, and 4 mg/ml). When used at 4 mg/ml, HA inhibits p-p38 phosphorylation by more than 60%. In response to IL-1 beta, RA chondrocytes express a higher level of p-p38 than that of OA chondrocytes. Inhibition of CD44, using a blocking antibody, significantly reversed the inhibitory effect of HA on both MMP-13 and p-p38. Our study clearly shows that HA inhibits IL-1 beta-induced MMP-13 via its principal receptor, CD44, and subsequent intracellular p38 MAPK signaling in OA and RA chondrocytes. (C) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 29: 258-264, 2011