Integrin-dependent functions of the angiogenic inducer NOV (CCN3) - Implication in wound healing
Integrin-dependent functions of the angiogenic inducer NOV (CCN3) - Implication in wound healing
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DOI：
10.1074/jbc.m404903200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Lin, CG;Chen, CC;Lau, LF
新型血管生成诱导剂CCN 3（NOV，肾母细胞瘤过度表达）是CCN家族的基质细胞蛋白，该家族还包括CCN 1（CYR 61）、CCN 2（CTGF）、CCN 4（WISP-1）、CCN 5（WISP-2）和CCN 6（WISP-3）。CCN 3在哺乳动物发育过程中在所有三个胚层的衍生物中广泛表达，其紊乱的表达与血管损伤和广泛的肿瘤相关。我们已经表明，CCN 3通过整联蛋白受体促进血管内皮细胞中的促血管生成活性并诱导体内新血管形成（Lin，C. G.，Leu，S. J.，Chen，N.，中国科学院院士，特博角M.，Lin，S. X.，杨角是的，和Lau，L. F.（2003）J.Biol.Chem.278，24200-24208）。在这项研究中，我们表明CCN 3在损伤后5-7天在皮肤伤口的肉芽组织中高度表达，并且能够诱导与伤口愈合一致的原代成纤维细胞中的反应。纯化的CCN 3通过整合素α（5）β（1）和α（6）β（1）支持原代皮肤成纤维细胞粘附，并通过整合素α（v）β（5）诱导成纤维细胞趋化性。我们表明，CCN 3是一种新的α（v）β（5）在固相结合试验的配体。虽然CCN 3本身不促有丝分裂，但它也能增强碱性成纤维细胞生长因子诱导的DNA合成。此外，CCN 3上调MMP-1和派-1表达，但以拮抗或协同方式与TGF-β 1相互作用以调节特定基因的表达。这些发现，连同其血管生成活性，支持CCN 3在皮肤成纤维细胞中的皮肤伤口愈合中的作用，并通过整联蛋白受体建立其基质细胞作用模式。
The novel angiogenic inducer CCN3 ( NOV, nephroblastoma overexpressed) is a matricellular protein of the CCN family, which also includes CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3). CCN3 is broadly expressed in derivatives of all three germ layers during mammalian development, and its deranged expression is associated with vascular injury and a broad range of tumors. We have shown that CCN3 promotes proangiogenic activities in vascular endothelial cells through integrin receptors and induces neovascularization in vivo (Lin, C. G., Leu, S. J., Chen, N., Tebeau, C. M., Lin, S. X., Yeung, C. Y., and Lau, L. F. (2003) J. Biol. Chem. 278, 24200-24208). In this study, we show that CCN3 is highly expressed in granulation tissue of cutaneous wounds 5-7 days after injury and is capable of inducing responses in primary fibroblasts consistent with wound healing. Purified CCN3 supports primary skin fibroblast adhesion through integrins alpha(5)beta(1) and alpha(6)beta(1) and induces fibroblast chemotaxis through integrin alpha(v)beta(5). We show that CCN3 is a novel ligand of alpha(v)beta(5) in a solid phase binding assay. Although not mitogenic on its own, CCN3 also enhances basic fibroblast growth factor-induced DNA synthesis. Furthermore, CCN3 up-regulates MMP-1 and PAI-1 expression but interacts with TGF-beta1 in an antagonistic or synergistic manner to regulate the expression of specific genes. These findings, together with its angiogenic activity, support a role for CCN3 in cutaneous wound healing in skin fibroblasts and establish its matricellular mode of action through integrin receptors.