Leni and Peter W. May Department of Orthopedics, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029, USA.
FASEB J. 2011 Jan;25(1):182-91. doi: 10.1096/fj.10-164277. Epub 2010 Sep 8.
Both overuse and disuse of joints up-regulate matrix metalloproteinases (MMPs) in articular cartilage and cause tissue degradation; however, moderate (physiological) loading maintains cartilage integrity. Here, we test whether CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), a mechanosensitive transcriptional coregulator, mediates this chondroprotective effect of moderate mechanical loading. In vivo, hind-limb immobilization of Sprague-Dawley rats up-regulates MMP-1 and causes rapid, histologically detectable articular cartilage degradation. One hour of daily passive joint motion prevents these changes and up-regulates articular cartilage CITED2. In vitro, moderate (2.5 MPa, 1 Hz) intermittent hydrostatic pressure (IHP) treatment suppresses basal MMP-1 expression and up-regulates CITED2 in human chondrocytes, whereas high IHP (10 MPa) down-regulates CITED2 and increases MMP-1. Competitive binding and transcription assays demonstrate that CITED2 suppresses MMP-1 expression by competing with MMP transactivator, Ets-1 for its coactivator p300. Furthermore, CITED2 up-regulation in vitro requires the p38δ isoform, which is specifically phosphorylated by moderate IHP. Together, these studies identify a novel regulatory pathway involving CITED2 and p38δ, which may be critical for the maintenance of articular cartilage integrity under normal physical activity levels.
关节的过度使用和不使用都会使关节软骨中的基质金属蛋白酶（MMPs）上调，导致组织降解；然而，适度（生理性）的负荷能维持软骨的完整性。在这里，我们测试了 CBP/p300 相互作用的转录共激活因子，富含 ED 的尾巴 2（CITED2），一种机械敏感的转录共调节因子，是否介导了适度机械负荷对软骨的保护作用。在体内，Sprague-Dawley 大鼠的后肢固定会使 MMP-1 上调，并导致快速的、组织学上可检测到的关节软骨降解。每天 1 小时的被动关节运动可预防这些变化，并上调关节软骨 CITED2。在体外，适度（2.5 MPa，1 Hz）间歇性静压（IHP）处理抑制人软骨细胞中 MMP-1 的基础表达，并上调 CITED2，而高 IHP（10 MPa）则下调 CITED2 并增加 MMP-1。竞争结合和转录分析表明，CITED2 通过与 MMP 转录激活因子 Ets-1 竞争其共激活剂 p300 来抑制 MMP-1 的表达。此外，体外 CITED2 的上调需要 p38δ 同工型，它是由适度 IHP 特异性磷酸化的。综上所述，这些研究确定了一种涉及 CITED2 和 p38δ 的新的调节途径，这对于在正常身体活动水平下维持关节软骨的完整性可能是至关重要的。
