Effects of rhDecorin on TGF-β1 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
Source: PubMed

ABSTRACT 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.

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    • "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). "
    Hepatocellular Carcinoma - Basic Research, 02/2012; , ISBN: 978-953-51-0023-2
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    • "Decorin interacts with the epidermal growth factor (EGF) receptor ErbB2 [11] and TGFb [5] [12] [13], cytokines with an important function on proliferation, migration, and differentiation of human keratinocytes. Decorin is found in extracellular dermal components of skin, but not in contact with the epidermal keratinocytes. "
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    ABSTRACT: In various cell types, including cancer cells, decorin is involved in regulation of cell attachment, migration and proliferation. In skin, decorin is seen in dermis, but not in keratinocytes. We show that decorin gene (DCN) is expressed in the cultured keratinocytes, and the protein is found in the cytoplasm of differentiating keratinocytes and in suprabasal layers of human epidermis. RT-PCR experiments showed that DCN expression is regulated by pro-inflammatory and proliferative cytokines. Our data suggest that decorin should play a significant role in keratinocyte terminal differentiation, cutaneous homeostasis and dermatological diseases.
    Biochemical and Biophysical Research Communications 06/2011; 411(1):168-74. DOI:10.1016/j.bbrc.2011.06.122 · 2.28 Impact Factor
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    • "In several models of fibrosis it was shown that treatment with decorin considerably attenuated fibrogenesis, regardless of tissue and mode of decorin administration (Al Haj Zen et al. 2006, Border et al. 1992; Fukui et al. 2001; Grisanti et al. 2005; Huijun et al. 2005; Isaka et al. 1996; Kolb et al. 2001; Krishna et al. 2006). Two decades of investigations, after the initial observation by Border et al. (1992) confirmed the antifibrotic effects of decorin in a host of organs, such as the kidney (Schaefer et al. 2002; Williams et al. 2007), lung (Kolb et al. 2001), heart (Weis et al. 2005), skeletal muscle (Brandan et al. 2008), liver (Shi et al. 2006), blood vessels (Al Haj Zen et al. 2006), skin (Krishna et al. 2006), and conjunctiva (Grisanti et al. 2005). Furthermore, our understanding of the underlying mechanisms have improved considerably. "
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    ABSTRACT: The small leucine-rich proteoglycans (SLRPs) are biologically active components of the extracellular matrix (ECM), consisting of a protein core with leucine rich-repeat (LRR) motifs covalently linked to glycosaminoglycan (GAG) side chains. The diversity in composition resulting from the various combinations of protein cores substituted with one or more GAG chains along with their pericellular localization enables SLRPs to interact with a host of different cell surface receptors, cytokines, growth factors, and other ECM components, leading to modulation of cellular functions. SLRPs are capable of binding to: (i) different types of collagens, thereby regulating fibril assembly, organization, and degradation; (ii) Toll-like receptors (TLRs), complement C1q, and tumor necrosis factor-alpha (TNFalpha), regulating innate immunity and inflammation; (iii) epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), and c-Met, influencing cellular proliferation, survival, adhesion, migration, tumor growth and metastasis as well as synthesis of other ECM components; (iv) low-density lipoprotein receptor-related protein (LRP-1) and TGF-beta, modulating cytokine activity and fibrogenesis; and (v) growth factors such as bone morphogenic protein (BMP-4) and Wnt-I-induced secreted protein-1 (WISP-1), controlling cell proliferation and differentiation. Thus, the ability of SLRPs, as ECM components, to directly or indirectly regulate cell-matrix crosstalk, resulting in the modulation of various biological processes, aptly qualifies these compounds as matricellular proteins.
    Journal of Cell Communication and Signaling 10/2009; 3(3-4):323-35. DOI:10.1007/s12079-009-0066-2
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