COMP-Ang1 enhances DNA synthesis and cell cycle progression in human periodontal ligament cells via Tie2-mediated phosphorylation of PI3K/Akt and MAPKs
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- 作者：Shin-Saeng Lim ; Sung-Ho Kook ; Jeong-Chae Lee
- 刊名：Molecular and Cellular Biochemistry
- 出版年：2016
- 出版时间：May 2016
- 年：2016
- 卷：416
- 期：1-2
- 页码：157-168
- 全文大小：3,142 KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Life Sciences
Biochemistry
Medical Biochemistry
Oncology
Cardiology - 出版者：Springer Netherlands
- ISSN：1573-4919
- 卷排序：416
文摘
Recombinant COMP-Ang1, a chimera of angiopoietin-1 (Ang1), and a short coiled-coil domain of cartilage oligomeric matrix protein (COMP) can stimulate multiple cellular processes. Proliferative capacity of periodontal ligament (PDL) fibroblasts (PLFs) is important for maintaining PDL integrity and homeostasis. In this study, we explored whether exogenous COMP-Ang1 addition enhances proliferation of human PLFs and the cellular mechanisms therein. We initially isolated and characterized PLFs, where the cells showed highly positive staining for surface markers, CD90, CD105, and CD146. COMP-Ang1 treatment increased proliferation of PLFs by stimulating migration of cells into S and G2/M phases. This increase was coupled with decreased p21Cip and p27Kip levels and enhanced cyclin D1, cyclin-dependent kinase (CDK) 2, and CDK4 induction. Transfection with si-Tie2 near completely blocked COMP-Ang1-stimulated cell cycle progression in PLFs. Tie2 knockdown also inhibited COMP-Ang1-induced phosphorylation of mitogen-activated protein kinases (MAPKs). In addition, COMP-Ang1-mediated activation of Akt and c-Jun was suppressed by treating each of pharmacological inhibitors specific to phosphoinositide 3-kinase (PI3K) (LY294002 and Wortmannin) or MAPKs (PD98059, SB203580, and SP600125). Similarly, COMP-Ang1-mediated increases in DNA synthesis and cyclin D1 induction were prevented by treating inhibitor of MAPKs and PI3K or by c-Jun knockdown. These results suggest that COMP-Ang1 enhances survival and proliferation of human PLFs through the activation of Tie2-mediated signaling, where PI3K/Akt and MAPK-c-Jun signaling pathways act as downstream effectors. Collectively, COMP-Ang1 may be a useful as a stimulator of human PLFs and therefore improves PDL integrity and homeostasis.KeywordsCOMP-Ang1Human periodontal ligament fibroblastsTie2ProliferationCell cycle regulatory factorsSignal transduction pathway