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PI3K 在小鼠生长板软骨细胞中对基因表达的调控。

Regulation of gene expression by PI3K in mouse growth plate chondrocytes.

机构信息

CIHR Group in Skeletal Development and Remodeling, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

出版信息

PLoS One. 2010 Jan 25;5(1):e8866. doi: 10.1371/journal.pone.0008866.

Abstract

BACKGROUND

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.

METHODOLOGY/PRINCIPAL FINDINGS: 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.

CONCLUSIONS/SIGNIFICANCE: 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.

摘要

背景

软骨内骨化是长骨形成的过程,涉及软骨细胞在软骨生长板中的增殖和肥大分化。在之前的一篇出版物中,我们表明,PI3K 信号通路的药理学抑制会导致软骨内骨生长减少,特别是在胫骨器官培养系统中,肥大区缩短。在本研究中,我们旨在研究 PI3K 信号通路在肥大软骨细胞中的靶点。

方法/主要发现: 通过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(用 PI3K 药理学抑制剂处理的原代软骨细胞和微解剖的生长板)的交叉,我们能够识别出大量的基因,这些基因被归类为 GSEA 功能类别,受 PI3K 信号通路调控。PI3K 抑制后,如 Phlda2 和 F13a1 等基因下调,在生长板的增殖/静止区与肥大区相比,表达增加。相比之下,其他基因,如 Nr4a1 和 Adamts5,在 PI3K 抑制后上调,在肥大区表达减少。这些基因受 PI3K 信号的调控通过定量 RT-PCR 得到了证实。我们之所以关注 F13a1,是因为它在软骨细胞肥大和骨关节炎中具有已知的作用。用 LY294002(PI3K 抑制剂)培养 E15.5 天的小鼠胫骨 6 天后,与对照培养物相比,肥大区的因子 XIIIa 表达减少。

结论/意义: 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,并更好地理解软骨环境,以用于组织工程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8663/2810323/f2fe4018da3a/pone.0008866.g001.jpg

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