Connective tissue growth factor mediates transforming growth factor β-induced collagen synthesis:: downregulation by cAMP
Connective tissue growth factor mediates transforming growth factor β-induced collagen synthesis:: downregulation by cAMP
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DOI：
10.1096/fasebj.13.13.1774
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发表时间：
1999-10-01
期刊：
影响因子：
4.8
通讯作者：
Grotendorst, GR
中科院分区：
文献类型：
--
作者：
Duncan, MR;Frazier, KS;Grotendorst, GR
结缔组织生长因子（CTGF）是一种富含半胱氨酸的肽，由成纤维细胞在转化生长因子β (tgf - β)激活后合成和分泌，是tgf - β诱导成纤维细胞增殖的下游介质。我们进行了体外和体内研究，以确定CTGF是否也是tgf - β诱导的成纤维细胞胶原合成所必需的。正常大鼠肾（NRK）成纤维细胞的体外研究表明，CTGF能有效诱导胶原合成，转染反义CTGF基因可阻断tgf - β刺激的胶原合成。此外，NRK和人包皮成纤维细胞中tgf - β诱导的胶原合成均被特异性抗CTGF抗体有效阻断，并通过膜透性8-Br-cAMP或腺苷酸环化酶激活剂霍乱毒素（CTX）提高细胞内cAMP水平来抑制tgf - β诱导的CTGF基因表达。与之前报道的cAMP对CTGF诱导的DNA合成缺乏影响不同，cAMP还能抑制CTGF自身诱导的胶原合成。在动物实验中，转基因小鼠皮内注射CTX可抑制人CTGF启动子/lacZ报告基因的tgf - β激活。8-Br-cAMP和CTX均可阻断大鼠创伤室纤维化模型中tgf - β诱导的胶原沉积。CTX还能减少新生小鼠由tgf - β诱导的真皮肉芽组织成纤维细胞数量的增加，但对CTGF或tgf - β联合CTGF诱导的增加没有影响。我们的数据表明，CTGF介导tgf - β诱导的成纤维细胞胶原合成，体内阻断CTGF的合成或作用通过抑制胶原合成和成纤维细胞积累来减少tgf - β诱导的肉芽组织形成。
Connective tissue growth factor (CTGF) is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with transforming growth factor beta (TGF-beta) that acts as a downstream mediator of TGF-beta-induced fibroblast proliferation. We performed in vitro and in vivo studies to determine whether CTGF is also essential for TGF-beta-induced fibroblast collagen synthesis. lit vitro studies with normal rat kidney (NRK) fibroblasts demonstrated CTGF potently induces collagen synthesis and transfection with an antisense CTGF gene blocked TGF-beta stimulated collagen synthesis. Moreover, TGF-beta-induced collagen synthesis in both NRK and human foreskin fibroblasts was effectively blocked with specific anti-CTGF antibodies and by suppressing TGF-beta-induced CTGF gene expression by elevating: intracellular cAMP levels with either membrane-permeable 8-Br-cAMP or an adenylyl cyclase activator, cholera toxin (CTX). cAMP also inhibited collagen synthesis induced by CTGF itself, in contrast to its previously reported lack of effect on CTGF-induced DNA synthesis. In animal assays, CTX injected intradermally in transgenic mice suppressed TGF-beta activation of a human CTGF promoter/lacZ reporter transgene. Both 8-Br-cAMP and CTX blocked TGF-beta-induced collagen deposition in a wound chamber model of fibrosis in rats. CTX also reduced dermal granulation tissue fibroblast population increases induced by TGF-beta in neonatal mice, but not increases induced by CTGF or TGF-beta com bined with CTGF. Our data indicate that CTGF mediates TGF-beta-induced fibroblast collagen synthesis and that in vivo blockade of CTGF synthesis or action reduces TGF-beta-induced granulation tissue formation by inhibiting both collagen synthesis and fibroblast accumulation.