Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis.
Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis.
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DOI：
10.1002/art.24225
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发表时间：
2009-02
影响因子：
--
通讯作者：
Loeser, Richard F.
中科院分区：
文献类型：
--
作者：
Cravero, John D.;Carlson, Cathy S.;Im, Hee-Jeong;Yammani, Raghunatha R.;Long, David;Loeser, Richard F.
软骨细胞对IGF-1的反应随着衰老和OA而降低。IGF-1通过PI-3激酶/Akt途径进行信号传导。TRB 3是一种tribbles同源物，已显示抑制HEK 293细胞中IGF-1对Akt的激活。在这项研究中，我们确定了TRB 3是否在软骨细胞中表达，以及TRB 3是否降低了软骨细胞对IGF-1的反应。使用从组织供体获得的正常人关节软骨和从膝关节置换手术获得的OA组织通过RT-PCR、免疫印迹和免疫组织化学测量TRB 3。通过瞬时转染过表达TRB 3来确定TRB 3对细胞存活和蛋白聚糖合成的影响。在正常人软骨细胞中检测到TRB 3 RNA。TRB 3蛋白水平在正常软骨细胞中较低，但在OA细胞中显著增加。与两种诱导内质网应激的试剂，衣霉素和毒胡萝卜素一起孵育，增加了正常细胞中的TRB 3水平。TRB 3过表达抑制Akt磷酸化，降低软骨细胞存活率和蛋白多糖合成。这些结果首次证明TRB 3存在于人软骨细胞中，并且其水平在OA软骨和分离的OA软骨细胞中增加。因为它是Akt激活的抑制剂，所以TRB 3水平的增加可能在OA软骨中观察到的细胞死亡增加以及对IGF-1的反应降低中起作用。
The chondrocyte response to IGF-1 is reduced with aging and in OA. IGF-1 signals through the PI-3 kinase/Akt pathway. TRB3, a tribbles homolog, has been shown to inhibit IGF-1 activation of Akt in HEK293 cells. In this study, we determined if TRB3 is expressed in chondrocytes and if TRB3 reduces the chondrocyte response to IGF-1. Normal human articular cartilage obtained from tissue donors and OA tissue obtained from knee replacement surgery were used to measure TRB3 by RT-PCR, immunoblotting, and immunohistochemistry. Overexpression of TRB3 by transient transfection was used to determine the effects of TRB3 on cell survival and proteoglycan synthesis. TRB3 RNA was detected in normal human chondrocytes. TRB3 protein levels were low in cells from normal cartilage but significantly increased in OA cells. Incubation with two agents that induce endoplasmic reticulum stress, tunicamycin and thapsigargin, increased TRB3 levels in normal cells. Overexpression of TRB3 inhibited Akt phosphorylation and reduced chondrocyte survival and proteoglycan synthesis. These results are the first to demonstrate that TRB3 is present in human chondrocytes and its level is increased in OA cartilage and isolated OA chondrocytes. Because it is an inhibitor of Akt activation, increased levels of TRB3 could play a role in the increased cell death as well as the reduced response to IGF-1 seen in OA cartilage.
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