Effects of rhDecorin on TGF-_1 induced human hepatic stellate cells LX-2 activation
The Chinese University of Hong Kong, Hong Kong, 00, Hong Kong Biochimica et Biophysica Acta
(Impact Factor: 4.66).
12/2006; 1760(11):1587-95. DOI: 10.1016/j.bbagen.2006.09.012
Decorin is a small leucine-rich extracellular matrix proteoglycan composed of a core protein with a single glycosaminoglycan (GAG) chain near the N-terminus and N-glycosylated at three potential sites. Decorin is involved in the regulation of formation and organization of collagen fibrils, modulation of the activity of growth factors such as transforming growth factor beta (TGF-beta), and exerts other effects on cell proliferation and behavior. Increasing evidences show that decorin plays an important role in fibrogenesis by regulating TGF-beta, a key stimulator of fibrosis, and by directly modulating the degradation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). In this study, the core protein of human decorin was cloned and expressed in Escherichia coli. The purified recombinant human decorin (rhDecorin) significantly inhibited the proliferation of LX-2 cells, a human HSC cell line, stimulated by TGF-beta1. RT-PCR result showed that the expression of metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were reduced by rhDecorin in LX-2 cells stimulated by TGF-beta1. Furthermore, the protein expression of smooth muscle-alpha-actin (alpha-SMA), collagen type III and phosphorylated Smad2 (p-Smad2) was significantly decreased in the presence of rhDecorin. rhDecorin also reduced fibrillogenesis of collagen type I in a dose-dependent manner. Gene expression profiles of LX-2 cells stimulated by TGF-beta1 in the presence and the absence of rhDecorin were obtained by using cDNA microarray technique and differentially expressed genes were identified to provide further insight into the molecular action mechanism of decorin on LX-2 cells.
Available from: Qian Zhong-Ji
- "TIMPs, specific inhibitors of MMPs, have been identified as the important regulators of MMP activity and ECM degradation (13). Expression of TIMP-1 and MMP-2 is increased in hepatic fibrosis, which reflects the changes of hepatic fibrosis (14,15). In our study, Western blot and RT-PCR results showed that NIPP-1 significantly inhibited mRNA expression of TIMP-1 and MMP-2, which were up-regulated under TGF-β1 stimulation, suggesting that NIPP-1 has the ability of modulating or attenuating TGF-β1 activity (Fig. 7). "
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ABSTRACT: In this study, novel peptides (NIPP-1, NIPP-2) derived from Navicula incerta (microalgae) protein hydrolysate were explored for their inhibitory effects on collagen release in hepatic fibrosis with the investigation of its underlying mechanism of action. TGF-β1 activated fibrosis in LX-2 cells was examined in the presence or absence of purified peptides NIPP-1 and NIPP-2. Besides the mechanisms of liver cell injury, protective effects of NIPP-1 and NIPP-2 were studied to show the protective mechanism against TGF-β1 stimulated fibrogenesis. Our results showed that the core protein of NIPP-1 peptide prevented fibril formation of type I collagen, elevated the MMP level and inhibited TIMP production in a dose-dependent manner. The treatment of NIPP-1 and NIPP-2 on TGF-β1 induced LX-2 cells alleviated hepatic fibrosis. Moreover, α-SMA, TIMPs, collagen and PDGF in the NIPP-1 treated groups were significantly decreased. Therefore, it could be suggested that NIPP-1 has potential to be used in anti-fibrosis treatment.
Available from: Inge Mannaerts
- "Ever since the contribution of HSCs to matrix deposition and liver fibrosis was discovered, attempts to inhibit their activation have been made. Evidence for anti-fibrotic properties of drugs affecting HSC activation is mostly limited to in vitro data , , , , , , , , . Our experience with MC1568 shows that the in vitro anti-fibrotic potential of a given compound cannot always be translated to in vivo benefits due to impending problems in stability, turnover or delivery to the HSCs. "
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ABSTRACT: The conversion of a quiescent vitamin A storing hepatic stellate cell (HSC) to a matrix producing, contractile myofibroblast-like activated HSC is a key event in the onset of liver disease following injury of any aetiology. Previous studies have shown that class I histone deacetylases (HDACs) are involved in the phenotypical changes occurring during stellate cell activation in liver and pancreas.
In the current study we investigate the role of class II HDACs during HSC activation.
We characterized the expression of the class II HDACs freshly isolated mouse HSCs. We inhibited HDAC activity by selective pharmacological inhibition with MC1568, and by repressing class II HDAC gene expression using specific siRNAs.
Inhibition of HDAC activity leads to a strong reduction of HSC activation markers α-SMA, lysyl oxidase and collagens as well as an inhibition of cell proliferation. Knock down experiments showed that HDAC4 contributes to HSC activation by regulating lysyl oxidase expression. In addition, we observed a strong up regulation of miR-29, a well-known anti-fibrotic miR, upon treatment with MC1568. Our in vivo work suggests that a successful inhibition of class II HDACs could be promising for development of future anti-fibrotic compounds.
In conclusion, the use of MC1568 has enabled us to identify a role for class II HDACs regulating miR-29 during HSC activation.
Available from: Ilona Kovalszky
- "While the net outcome of these interactions depends on the cell type, decorin seemed to inhibit TGF-β1- dependent fibroblast proliferation and matrix production in the context of experimental renal fibrogenesis (Isaka et al., 1996). Importantly, decorin exerted a similar inhibitory effect on a human hepatic stellate cell (HSC) line in vitro (Shi et al., 2006). Since activated hepatic stellate cells are the major culprits in liver fibrosis, decorin might limit worsening of the condition, and the use of decorin as a TGF-β1 blocking agent for the treatment of chronic liver disease has been repeatedly proposed (Breitkopf et al., 2005). "
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