Transcription factor Nfat1 deficiency causes osteoarthritis through dysfunction of adult articular chondrocytes.
Transcription factor Nfat1 deficiency causes osteoarthritis through dysfunction of adult articular chondrocytes.
复制标题
DOI：
10.1002/path.2578
复制
发表时间：
2009-10
影响因子：
7.3
通讯作者：
Anderson, Harrison C.
中科院分区：
文献类型：
--
作者：
Wang, Jinxi;Gardner, Brian M.;Lu, Qinghua;Rodova, Marianna;Woodbury, Brent G.;Yost, John G.;Roby, Katherine F.;Pinson, David M.;Tawfik, Ossama;Anderson, Harrison C.
关键词：
骨关节炎（OA）是中老年人最常见的关节疾病形式。先前的研究表明，基质降解蛋白酶和促炎细胞因子的过度表达与骨关节炎软骨降解有关。然而，目前尚不清楚哪些转录因子调节关节软骨细胞中这些软骨降解分子的表达。本研究表明，缺乏活化T细胞的核因子（NFAT）转录因子成员Nfat1的小鼠，骨骼发育正常，但在负重关节的年轻成年关节软骨中，Ⅱ型胶原蛋白（胶原蛋白 - 2）和聚集蛋白聚糖缺失，同时特定基质降解蛋白酶和促炎细胞因子过度表达。这些初始变化之后是关节软骨细胞增殖/聚集、关节表面进行性破坏、关节周围软骨骨赘形成以及增厚的软骨下骨暴露，所有这些都类似于人类OA。用慢病毒载体在培养的3个月大的原发性Nfat1基因敲除（Nfat1 - / -）关节软骨细胞中强制表达Nfat1，部分或完全挽救了Nfat1 - / -关节软骨细胞的异常分解代谢和合成代谢活动。这些新发现揭示了Nfat1通过调节特定基质降解蛋白酶和促炎细胞因子的表达，在维持分化的成年关节软骨细胞生理功能方面先前未被认识到的关键作用。Nfat1缺乏导致OA是由于成年关节软骨细胞分解代谢和合成代谢活动之间的失衡，导致关节软骨降解以及关节软骨内部和周围修复活动失败。这些结果可能为骨关节炎的病因、发病机制和潜在治疗策略提供新的见解。
Osteoarthritis (OA) is the most common form of joint disease in middle-aged and older people. Previous studies have shown that over expression of matrix-degrading proteinases and proinflammatory cytokines is associated with osteoarthritic cartilage degradation. However, it remains unclear which transcription factors regulate the expression of these cartilage-degrading molecules in articular chondrocytes. This study demonstrated that mice lacking Nfat1, a member of the nuclear factor of activated T-cells (NFAT) transcription factors, exhibited normal skeletal development but displayed loss of type-II collagen (collagen-2) and aggrecan with overexpression of specific matrix-degrading proteinases and proinflammatory cytokines in young adult articular cartilage of weight-bearing joints. These initial changes are followed by articular chondrocyte proliferation/clustering, progressive articular surface destruction, periarticular chondro-osteophyte formation, and exposure of thickened subchondral bone, all of which resemble human OA. Forced expression of Nfat1 delivered with lentiviral vectors in cultured 3-month-old primary Nfat1 knockout (Nfat1−/−) articular chondrocytes partially or completely rescued the abnormal catabolic and anabolic activities of Nfat1−/− articular chondrocytes. These new findings revealed a previously unrecognized critical role of Nfat1 in maintaining the physiological function of differentiated adult articular chondrocytes through regulating the expression of specific matrix-degrading proteinases and proinflammatory cytokines. Nfat1 deficiency causes OA due to an imbalance between catabolic and anabolic activities of adult articular chondrocytes, leading to articular cartilage degradation and failed repair activities in and around articular cartilage. These results may provide new insights into the aetiology, pathogenesis and potential therapeutic strategies for osteoarthritis.
登录
查看更多内容
影响因子：
7
作者：
Kirsch, T;Swoboda, B;Nah, HD
通讯作者：
Nah, HD
影响因子：
9.7
作者：
Aoyama, T;Nagayama, S;Toguchida, J
通讯作者：
Toguchida, J
影响因子：
30.8
作者：
Bi, WM;Deng, JM;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
32.4
作者：
Hodge, MR;Ranger, AM;Glimcher, LH
通讯作者：
Glimcher, LH
DOI：
10.1097/01.blo.0000144854.66565.8f
发表时间：
2004-10-01
影响因子：
4.2
作者：
Goldring, SR;Goldring, MB
通讯作者：
Goldring, MB