Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways.
Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways.
复制标题
DOI：
10.1101/gad.231969.113
复制
发表时间：
2014-01-15
影响因子：
10.5
通讯作者：
Lassar AB
中科院分区：
文献类型：
--
作者：
Ogawa H;Kozhemyakina E;Hung HH;Grodzinsky AJ;Lassar AB
Prg 4基因座编码蛋白聚糖润滑素，可预防骨关节炎。Ogawa等发现跑步以考克斯-2依赖性方式诱导膝关节关节软骨浅表区中Prg 4的最大表达。这与CREB依赖性基因表达增加有关。流体流动剪切应力增加细胞外PGE 2、PTHrP和ATP的分泌，它们一起促进CREB依赖性的Prg 4诱导。这些结果表明，机械运动可能通过与体外流体流动剪切应力激活的相同信号通路诱导Prg 4表达。Lubricin是由Prg 4基因座编码的分泌性蛋白聚糖，其由浅区关节软骨细胞大量表达，并且已经注意到对机械负荷敏感并防止骨关节炎的发展。在这项研究中，我们的文件，运行诱导最大的表达Prg 4在膝关节软骨的浅区的考克斯-2依赖的方式，这与增强的磷酸-S133 CREB水平和增加的CREB调节的转录辅激活因子（CRTCs）在该组织中的核定位。此外，我们发现流体流动剪切应力（FFSS）增加细胞外PGE 2，PTHrP和ATP（由骺软骨细胞）的分泌，它们共同参与PKA和Ca++调节的信号通路，其组合起作用以促进CREB依赖的Prg 4诱导，特别是在浅区关节软骨细胞中。因为跑步和FFSS都以考克斯-2依赖的方式促进Prg 4的表达，我们的研究结果表明，机械运动可能通过参与体外激活的相同信号通路来诱导关节软骨浅表区的Prg 4表达，FFSS促进该组织中CREB依赖的基因表达。
The Prg4 locus encodes the proteoglycan lubricin that protects against osteoarthritis. Ogawa et al. discover that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion. This correlated with increased CREB-dependent gene expression. Fluid flow shear stress increases secretion of extracellular PGE2, PTHrP, and ATP, which together promote CREB-dependent induction of Prg4. These results suggest that mechanical motion may induce Prg4 expression through the same signaling pathways activated in vitro by fluid flow shear stress. Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca++-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.
登录
查看更多内容
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Cherian, PP;Siller-Jackson, AJ;Jiang, JX
通讯作者：
Jiang, JX
影响因子：
4.2
作者：
Li, J;Burr, DB;Turner, CH
通讯作者：
Turner, CH
影响因子：
4.8
作者：
Cherian, PP;Cheng, BX;Jiang, JX
通讯作者：
Jiang, JX
影响因子：
--
作者：
Chen, Xuesong;Macica, Carolyn M.;Nasiri, Ali;Broadus, Arthur E.
通讯作者：
Broadus, Arthur E.