Regulation of gene expression by PI3K in mouse growth plate chondrocytes.
Regulation of gene expression by PI3K in mouse growth plate chondrocytes.
复制标题
小鼠生长板软骨细胞中 PI3K 基因表达的调节。
DOI：
10.1371/journal.pone.0008866
复制
发表时间：
2010-01-25
期刊：
影响因子：
3.7
通讯作者：
Beier, Frank
中科院分区：
文献类型：
--
作者：
Ulici, Veronica;James, Claudine G.;Hoenselaar, Katie D.;Beier, Frank
软骨内骨化是长骨形成的过程，涉及软骨生长板中的软骨细胞增殖和肥大分化。在以前的出版物中，我们表明，药理学抑制PI 3 K信号通路导致软骨内骨生长减少，特别是胫骨器官培养系统中肥大区缩短。本研究旨在探讨肥大软骨细胞中PI 3 K信号通路的靶点。通过交叉两种不同的微阵列分析方法（经典的单基因分析和GSEA）和两种不同的软骨细胞分化系统（原代软骨细胞与PI 3 K和显微切割生长板的药理学抑制剂处理），我们能够识别大量的基因分组在GSEA功能类别的PI 3 K信号通路的调节。基因如Phlda 2和F13 a1在PI 3 K抑制后下调，并且与生长板的增殖/静止区相比，在肥大区中显示出增加的表达。相反，其他基因包括Nr 4a 1和Adamts 5在PI 3 K抑制后上调，并在肥大区中显示出表达减少。通过定量RT-PCR证实了这些基因通过PI 3 K信号传导的调节。我们将F13 a1作为一个有趣的靶点，因为它在软骨细胞肥大和骨关节炎中的作用是已知的。与对照培养物相比，用LY 294002（PI 3 K抑制剂）培养6天的小鼠E15.5抗体显示肥大区中因子XIIIa的表达降低。发现肥大软骨细胞中信号通路的靶点可能导致骨关节炎的靶向治疗，并更好地了解组织工程的软骨环境。
Endochondral ossification, the process through which long bones are formed, involves chondrocyte proliferation and hypertrophic differentiation in the cartilage growth plate. In a previous publication we showed that pharmacological inhibition of the PI3K signaling pathway results in reduced endochondral bone growth, and in particular, shortening of the hypertrophic zone in a tibia organ culture system. In this current study we aimed to investigate targets of the PI3K signaling pathway in hypertrophic chondrocytes. Through the intersection of two different microarray analyses methods (classical single gene analysis and GSEA) and two different chondrocyte differentiation systems (primary chondrocytes treated with a pharmacological inhibitor of PI3K and microdissected growth plates), we were able to identify a high number of genes grouped in GSEA functional categories regulated by the PI3K signaling pathway. Genes such as Phlda2 and F13a1 were down-regulated upon PI3K inhibition and showed increased expression in the hypertrophic zone compared to the proliferative/resting zone of the growth plate. In contrast, other genes including Nr4a1 and Adamts5 were up-regulated upon PI3K inhibition and showed reduced expression in the hypertrophic zone. Regulation of these genes by PI3K signaling was confirmed by quantitative RT-PCR. We focused on F13a1 as an interesting target because of its known role in chondrocyte hypertrophy and osteoarthritis. Mouse E15.5 tibiae cultured with LY294002 (PI3K inhibitor) for 6 days showed decreased expression of factor XIIIa in the hypertrophic zone compared to control cultures. Discovering targets of signaling pathways in hypertrophic chondrocytes could lead to targeted therapy in osteoarthritis and a better understanding of the cartilage environment for tissue engineering.
登录
查看更多内容
影响因子：
4.4
作者：
James CG;Ulici V;Tuckermann J;Underhill TM;Beier F
通讯作者：
Beier F
影响因子：
5.8
作者：
Al-Shahrour, F;Díaz-Uriarte, R;Dopazo, J
通讯作者：
Dopazo, J
影响因子：
4.8
作者：
Barthel, A;Okino, ST;Roth, RA
通讯作者：
Roth, RA
影响因子：
3
作者：
Kim, SY;Volsky, DJ
通讯作者：
Volsky, DJ
影响因子：
4.7
作者：
Apostolidou, S.;Abu-Amero, S.;Moore, G. F.
通讯作者：
Moore, G. F.