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PubMed2003

Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts.

Decorin is a small leucine-rich proteoglycan that plays a role in control of cell proliferation, cell migration, collagen fibrillogenesis and modulation of the activity of TGF-beta. In the present study, we investigated the effects of decorin on the production of metalloproteinases (MMP-1, -2, -3, -9 and -13), tissue inhibitors of metalloproteinases (TIMP-1, -2) and cytokines (TGF-beta, IL-1beta, IL-4 and TNF-alpha). Decorin was overexpressed in cultured human gingival fibroblasts using adenovirus-mediated gene transfer. Decorin infection resulted in decreased protein levels of MMP-1 and MMP-3 whereas MMP-2 and TIMP-2 secretion was increased. MMP-9, MMP-13 and TIMP-1 were not affected by decorin infection. Cytokine measurements by ELISA showed that decorin overexpression reduced TGF-beta and IL-1beta. In contrast, IL-4 and TNF-alpha levels were markedly increased in decorin-infected cells. These results suggest that decorin could modulate the expression of certain metalloproteinases and their inhibitors, as well as the production of cytokines. Altogether, our data suggest that decorin might play a pivotal role in tissue remodeling by acting on the balance between extracellular matrix synthesis and degradation.

Adenoviridae↗
PubMed1996

Decorin regulates collagenase gene expression in fibroblasts adhering to vitronectin.

Vitronectin, a principal cell adhesion molecule in plasma and extracellular matrix, mediates cell adhesion and spreading via the alpha V family of integrins. In this study we demonstrate that decorin, a small dermatan sulfate proteoglycan, regulates extracellular matrix remodeling in rabbit synovial fibroblasts adhering to vitronectin. Decorin induced the expression of the matrix metalloproteinase collagenase (MMP-1) when present on the substrate with vitronectin, or with the 120-kDa cell-binding domain of fibronectin, but not when present with intact fibronectin or Type I collagen. Secreted collagenase was detected within 8 h of adhesion, there was no associated alteration in cell shape or focal contact formation in cells adhering to decorin plus vitronectin, whereas cell rounding was observed in cells adhering to decorin plus the 120-kDa fragment of fibronectin. The core protein of decorin, but not the glycosaminoglycan moiety, was sufficient to induce collagenase expression on both substrates; however, the glycosaminoglycan moiety of decorin as well as the core were required for cell rounding observed in cells adhering to the 120-kDa domain of fibronectin. The collagenase-inducing effect of decorin seems to be independent of its effects on transforming growth factor-beta, as function-blocking antibodies against transforming growth factor-beta did not interfere with the collagenase-inducing effects of decorin. These data indicate that decorin has specific gene regulatory effects in cells when present in the matrix with vitronectin or the 120-kDa fragment of fibronectin, polypeptides that are present in actively remodeling tissues. Thus, in combination, these adhesion regulatory molecules transduce novel signals that may contribute to the tissue remodeling process in morphogenesis, wound healing and disease states.

Animals↗
PubMed1996

Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases.

The secreted proteoglycan decorin has been implicated in the negative control of cell proliferation primarily by virtue of its ability to block transforming growth factor-beta. Moreover, decorin expression is markedly up-regulated during quiescence but suppressed upon viral transformation, whereas de novo decorin expression in colon carcinoma cells abrogates the malignant phenotype by arresting the cells in the G1 phase of the cell cycle. Here we show that this decorin-induced growth arrest is associated with up-regulation of p21 mRNA and protein in a transforming growth factor-beta- and p53-independent pathway. The augmented p21 protein is present as a multimeric complex with various cyclins and cyclin-dependent kinases in the nuclei of decorin-expressing cells, thereby leading to suppression of cyclin-dependent kinase activity and block of cell division. Through the usage of decorin-specific antisense oligodeoxynucleotide treatment, we demonstrate that the expression of decorin is closely linked to that of p21 and that abrogation of decorin leads to suppression of p21 and restoration of cell division. Collectively, our results provide a plausible mechanism by which decorin may contribute to retard and suppress the growth of tumor cells in vivo.

Base Sequence↗
PubMed1996

Identification of a bimodal regulatory element encompassing a canonical AP-1 binding site in the proximal promoter region of the human decorin gene.

We have previously described a tumor necrosis factor alpha (TNF-alpha) response element, located between residues -188 and -140 of the human decorin promoter, that mediates the inhibitory effect of TNF-alpha on decorin gene expression (Mauviel, A., Santra, M., Chen, Y.-Q., Uitto, J., and Iozzo, R. V. (1995) J. Biol. Chem. 270, 11692-11700). In this report, we demonstrate that interleukin 1 (IL-1), a pleiotropic cytokine that shares a wide variety of biological properties with TNF-alpha, uses the same cis element to up-regulate decorin gene expression. Specifically, IL-1 enhances the expression of the human decorin gene, and this effect is mediated by activation of the corresponding promoter, as shown in transient cell transfection experiments using decorin promoter-chloramphenicol acetyl transferase reporter gene constructs. Additional transfection experiments with various 5'-deletion promoter-chloramphenicol acetyltransferase constructs demonstrate that both the inhibitory effect of TNF-alpha and the stimulatory effect of IL-1 are mediated by a 48-base pair segment of the promoter, between residues -188 and -140. This region, which contains a canonical AP-1 binding site, TGAGTCA, allows an antagonistic effect of these two cytokines on the decorin promoter activity. When cloned upstream of the thymidine kinase promoter, this promoter fragment requires the AP-1 sequence to be responsive to IL-1. Supershift assays with various AP-1 antibodies identified c-Jun, Jun-B, and Fra-1 as components of the complex binding to the decorin promoter. Overexpression of c-jun, an oncogene encoding the c-Jun/AP-1 transcription factor, reduces the basal activity of both decorin and -188/-140 thymidine kinase promoter constructs. In contrast, blockage of c-jun expression with an antisense c-jun construct potentiates the stimulatory effect of IL-1 and reverses the response to TNF-alpha. These data indicate that the region between residues -188 and -140 of the human decorin promoter functions as a bimodal regulatory element and allows transcriptional repression by c-Jun/AP-1 complexes.

Binding Sites↗
PubMed2001

Decorin-mediated signal transduction in endothelial cells. Involvement of Akt/protein kinase B in up-regulation of p21(WAF1/CIP1) but not p27(KIP1).

Endothelial cells undergoing angiogenesis express decorin, a small multifunctional proteoglycan. We have shown that decorin is causally involved in the formation of capillary-like structures and a decrease in apoptosis in endothelial cells cultured in a collagen lattice. Here we investigate signal transduction pathways mediating the effects of decorin. Reverse transcription-polymerase chain reaction demonstrated that p21 and p27, two inhibitors of cyclin-dependent kinases, were up-regulated by decorin induction. Decorin also increased protein levels of p21 and caused its translocation into the nucleus. p21 synthesis started 6 h after decorin addition and reached a plateau after 18 h, while cyclin A, which was also induced, peaked at 12 h and declined below basal levels within 24 h. These effects were mediated by the Akt/protein kinase B pathway. Akt phosphorylation at Thr-308 increased 4-fold and at Ser-473 1.4-fold within 10 min after decorin addition. Overexpression of dominant negative Akt inhibited the decorin-mediated induction of p21 and cyclin A, but had no effect on p27. These results show that decorin is a signaling molecule in sprouting endothelial cells where it acts via different pathways, one of them involving Akt/protein kinase B.

Base Sequence↗
PubMed2005

Decorin, a novel player in the insulin-like growth factor system.

Decorin is a multifunctional proteoglycan that is expressed by sprouting endothelial cells. Its expression supports capillary formation and cell survival. Previously, it was shown that some effects of decorin are mediated by protein kinase B and the cyclin-dependent kinase inhibitor, p21. However, the cell surface receptor responsible for these effects was unknown. We demonstrate that decorin binds to the insulin-like growth factor-I (IGF-I) receptor on endothelial cells with an affinity in the nanomolar range (K(D) = 18 nm), which is comparable with IGF-I (K(D) = 1.2 nm). Furthermore, decorin can bind IGF-I itself, but with a lower affinity (K(D) = 190 nm) than classical IGF-I-binding proteins. Decorin addition causes IGF-I receptor phosphorylation and activation, which is followed by receptor down-regulation. These effects are caused by the core protein of decorin, and the binding region could be mapped to the N terminus of the molecule. The physiological relevance of the decorin/IGF-I receptor interaction was corroborated in two animal models (e.g. inflammatory angiogenesis in the cornea and unilateral ureteral obstruction). In both models the IGF-I receptor was up-regulated in decorin-deficient mice compared with controls and the up-regulation could not compensate the decorin deficiency in the disease models. These data indicate that decorin is an important player in the IGF system and its loss cannot fully be compensated in different types of diseases.

Animals↗
PubMed2006

Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation.

Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg(-1)) every 2 days for 18-38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant down-regulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.

Animals↗
PubMed2006

Decorin modulates fibrin assembly and structure.

Emerging evidence indicates that fibrin clotting is regulated by different external factors. We demonstrated recently that decorin, a regulator of collagen fibrillogenesis and transforming growth factor-beta activity, binds to the D regions of fibrinogen (Dugan, T.A., Yang, V. W.-C., McQuillan, D.J., and Höök, M. (2003) J. Biol. Chem. 278, 13655-13662). We now report that the decorin-fibrinogen interaction alters the assembly, structure, and clearance of fibrin fibers. Relative to fibrinogen, substoichiometric amounts of decorin core protein modulated clotting, whereas an excess of an active decorin peptide was necessary for similar activity. These concentration-dependent effects suggest that decorin bound to the D regions sterically modulates fibrin assembly. Scanning electron microscopy images of fibrin clotted in the presence of increasing concentrations of decorin core protein showed progressively decreasing fiber diameter. The sequestration of Zn(2+) ions from the N-terminal fibrinogen-binding region abrogated decorin incorporation into the fibrin network. Compared with linear thicker fibrin fibers, the curving thin fibers formed with decorin underwent accelerated tissue-type plasminogen activator-dependent fibrinolysis. Collectively, these data demonstrate that decorin can regulate fibrin organization and reveal a novel mechanism by which extracellular matrix components can participate in hemostasis, thrombosis, and wound repair.

Binding Sites↗
PubMed2006

The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis.

BACKGROUND: Recurrent inflammation in chronic pancreatitis (CP) is not well understood. AIMS: To investigate whether decorin, an extracellular matrix (ECM) proteoglycan with macrophage modulating activity, is a pathogenic factor allowing diseased pancreatic stroma to sustain inflammation by affecting the cytokine profile of accumulating inflammatory cells. METHODS: Decorin was examined in 18 donors and 32 patients with CP by quantitative reverse transcription polymerase chain reaction (QRT-PCR), western blotting, and immunohistochemistry of pancreatic specimens. QRT-PCR was used to assess cytokine expression in donor peripheral blood mononuclear cells (PBMC), exposed or not to decorin in vitro, and to compare it with the cytokine profile of circulating and resident mononuclear cells (MNC) of patients with CP. RESULTS: In CP, desmoplasia is associated with overexpression of decorin in the growing ECM and enlarged pancreatic nerves. In culture, exposure of MNC to decorin stimulated expression of the MNC recruiting chemokine MCP-1. In biopsies, MNC infiltrates in decorin rich CP tissue showed a 300-fold upregulation of MCP-1 compared with decorin free peripheral blood, whereas no difference was found in basal MCP-1 expression in PBMC of patients versus donors. This effect was specific for MCP1-other inflammatory cytokines, such as interleukin 1beta and tumour necrosis factor alpha, were not affected. CONCLUSION: Decorin is a molecular marker of desmoplasia in CP, and excessive decorin may allow fibrotic masses to nourish and protract inflammation by deregulating the process of MNC accumulation and activation. These data provide a molecular basis for surgical resection of diseased tissue as a treatment option in CP.

Adolescent↗
PubMed1999

Adenovirus-mediated decorin gene transfer prevents TGF-beta-induced inhibition of lung morphogenesis.

Excessive transforming growth factor (TGF)-beta signaling has been implicated in pulmonary hypoplasia associated with bronchopulmonary dysplasia, a chronic lung disease of human prematurity featuring pulmonary fibrosis. This implies that inhibitors of TGF-beta could be useful therapeutic agents. Because exogenous TGF-beta ligands are known to inhibit lung branching morphogenesis and cytodifferentiation in mouse embryonic lungs in ex vivo culture, we examined the capacity of a naturally occurring inhibitor of TGF-beta activity, the proteoglycan decorin, to overcome the inhibitory effects of exogenous TGF-beta. Intratracheal microinjection of a recombinant adenovirus containing decorin cDNA resulted in overexpression of the exogenous decorin gene in airway epithelium. Although exogenous TGF-beta efficiently decreased epithelial lung branching morphogenesis in control cultures, TGF-beta-induced inhibition of lung growth was abolished after epithelial transfer of the decorin gene. Additionally, exogenous TGF-beta-induced antiproliferative effects as well as the downregulation of surfactant protein C were abrogated by decorin in cultured embryonic lungs. Moreover, lung branching inhibition by TGF-beta could be restored by the addition of decorin antisense oligodeoxynucleotides in culture, indicating that decorin is both specifically and directly involved in suppressing TGF-beta-mediated negative regulation of lung morphogenesis. Our findings suggest that decorin can antagonize bioactive TGF-beta during lung growth and differentiation, establishing the rationale for decorin as a candidate therapeutic approach to ameliorate excessive levels of TGF-beta signaling in the developing lung.

Adenoviridae↗
PubMed1998

Increased decorin mRNA in diabetic mouse kidney and in mesangial and tubular cells cultured in high glucose.

The core protein of the proteoglycan decorin binds and neutralizes transforming growth factor-beta (TGF-beta). Activation of TGF-beta is crucial to tissue injury in diabetic nephropathy, but it is not currently known whether decorin plays a role in this disease. Mouse kidney cortex demonstrates more than a twofold increase in decorin mRNA after 1, 2, 3, and 6 wk of streptozotocin diabetes. Various mouse and rat renal cell types are studied in culture under normal or high-glucose conditions. Mouse glomerular mesangial and proximal tubular epithelial cells constitutively express decorin, and high glucose (450 mg/dl) increases decorin mRNA fourfold compared with 100 mg/dl glucose. Unlike rat mesangial cells, rat glomerular epithelial and endothelial cells do not constitutively express decorin, and no induction is observed in high glucose. When mouse mesangial and proximal tubular cells are exposed to TGF-beta1 (1 ng/ml), decorin mRNA is significantly decreased. Our findings suggest that the increased decorin expression in the diabetic kidney may counteract the hypertrophic and prosclerotic effects of increased TGF-beta levels and that a negative feedback loop may exist between decorin and TGF-beta.

Animals↗
PubMed1997

Increased diameters of collagen fibrils precipitated in vitro in the presence of decorin from various connective tissues.

Proteoglycans were isolated from bovine skin, sclera, deep flexor tendon and the periphery of the temporomandibular joint disc with urea. Decorin was purified from each of these extracts by ion-exchange, hydrophobic-interaction and gel-filtration chromatography. Purities were assessed by amino acid analysis and by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) of the protein cores released by digestion with chondroitin-ABC-lyase. In these respects the decorins were indistinguishable. However the glycosaminoglycan chains released by digesting the proteoglycans with papain varied widely in mobility on SDS-PAGE: that from skin decorin migrating fastest and that from tendon decorin slowest. The effects of each of the decorins on collagen fibrillogenesis in vitro were similar, all reducing the rate of fibril growth (by 55 to 71%, depending on the source of the proteoglycan) and increasing the diameters of the fibrils formed (by 27 to 66%). Core protein alone, isolated from skin decorin, reduced the rate of fibril growth as effectively as intact decorin, but had no effect on the diameter of fibrils formed. The dermatan sulphate chain and the protein thus appear to play different roles in the interaction of intact decorin with collagen. These data suggest that decorin found in fibrous connective tissues may increase Type I collagen fibril diameters, resulting in tissues that are better able to withstand tensile forces.

Animals↗
PubMed2004

[The content of decorin and its mRNA expression in normal human skin and hyperplastic scars].

OBJECTIVE: To investigate the content of decorin and its mRNA expression in normal human skin and hyperplastic scars at different stages, so as to explore the relationship between the change of decorin and its synthesis. METHODS: Scar tissue samples from 22 patients undergoing scar excision and 10 specimens of normal skin or prepuce were obtained. The content and distribution of decorin in the tissue samples were determined with immunohistochemistry and Western blot, and the expression of decorin mRNA was detected by in situ hybridization. RESULTS: The content of decorin was rich in the normal skin dermis with lower expression of the mRNA. In contrast, the decorin content was scarce in hyperplastic scars (HS) within 6 months, but increased gradually beginning from 7 to 12 months, and increased continuously for 13 to 36 months. There was no difference between the decorin content in normal skin and that in HS after 36 months (P > 0.05). Furthermore, the mRNA expression level in HS tissue was lower than that in normal skin within 6 months, but increased from 7 to 12 months. The mRNA expression continuously increased during 13 to 36 months and then returned to the level similar to that in normal skin thereafter. CONCLUSION: The decrease of decorin in hyperplastic scar was resulted primarily from reduced synthesis. The increase in decorin level coincided with the time of scar tissue stabilization, which implied that the delayed appearance was correlated with the formation of HS.

Blotting, Western↗
PubMed1996

Deficient expression of the small proteoglycan decorin in a case of severe/lethal osteogenesis imperfecta.

In osteogenesis imperfecta (OI) the effects of mutations in type I collagen genes generally reflect their nature and localization. Unrelated individuals sharing identical mutations present, in general, similar clinical phenotypes. However, in some such cases the clinical phenotype differs. This variable clinical expression could be the result of abnormalities in other connective tissue proteins. Since decorin is a component of connective tissue, binds to type I collagen fibrils and plays a role in matrix assembly, we studied decorin production in skin fibroblasts from OI patients. Cultured fibroblasts from one patient with extremely severe osteogenesis imperfecta (classified as type II/III) who has an alpha 1(I)gly415ser mutation were found to secrete barely detectable amounts of decorin into culture medium. Western blotting using antibodies raised against decorin confirmed the reduction of the decorin core protein and Northern blot analysis showed decorin mRNA levels below the limit of detection. Cells from a patient, with a less severe phenotype, bearing a mutation in the same position of the triple helix (alpha 1(I)gly415) expressed decorin normally. The different clinical phenotypes could be due to the differing genetic backgrounds of the patients so it is tempting to conclude that in our most severely affected patient the absence of decorin aggravates the clinical phenotype.

Blotting, Northern↗
PubMed1998

Effects of interferon-gamma and tumor necrosis factor alpha on the expression of the genes encoding aggrecan, biglycan, and decorin core proteins in cultured human chondrocytes.

OBJECTIVE: To determine the effects of interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha), alone or in combination, on the expression of aggrecan, biglycan, and decorin core protein genes in human chondrocytes. METHODS: Isolated human chondrocytes were cultured on poly(2-hydroxyethyl methacrylate)-coated plastic dishes to prevent the loss of cartilage-specific phenotype, and the effects of IFN gamma and TNF alpha, alone or in combination, on aggrecan, biglycan, and decorin core protein gene transcription and steady-state messenger RNA (mRNA) levels were examined. RESULTS: The addition of IFN gamma (1.5 pM) or TNF alpha (0.3 pM) caused a decrease in the steady-state level of aggrecan mRNA (-25% and -15%, respectively), and the combination of these low-concentration cytokines caused a potent inhibition (-66%). These effects were the result of a decrease (-50%) in the transcription rate of the corresponding gene. At the concentrations used, IFN gamma did not alter the levels of biglycan mRNA or the transcription rates of the biglycan core protein gene. In contrast, TNF alpha decreased biglycan steady-state mRNA levels (-62%) and the biglycan core protein gene transcription rate (-18%). The combination of IFN gamma and TNF alpha resulted in a potentiation of the inhibitory effects of TNF alpha on biglycan mRNA levels (-79%) and transcription rate of the biglycan core protein gene (-46%). IFN gamma produced a modest decrease in decorin mRNA levels (-23%) and decorin core protein gene transcription rate (-17%). In contrast, TNF alpha resulted in a marked increase in decorin mRNA levels (+260%) that was not the result of transcriptional regulation. Notably, the combination of IFN gamma and TNF alpha potentiated the inhibitory effects of IFN gamma on decorin mRNA (-80%) and on the transcription of the corresponding gene (-43%). Similar results were obtained in fetal and adult articular chondrocytes. CONCLUSION: These data demonstrate that 1) the expression of the core protein genes encoding the cartilage proteoglycans aggrecan, biglycan, and decorin is differentially regulated by IFN gamma and TNF alpha; 2) these effects are mediated by transcriptional and posttranscriptional mechanisms; and 3) the combination of the 2 cytokines causes a potent inhibitory effect on the expression of the genes for the core proteins of these 3 proteoglycans, which occurs largely at the transcriptional level. The inhibition of aggrecan, decorin, and biglycan core protein gene expression by the combination of IFN gamma and TNF alpha may contribute to the cartilage destruction that is characteristic of inflammatory joint diseases.

Adult↗
PubMed1996

Purification and characterization of decorin core protein expressed in Escherichia coli as a maltose-binding protein fusion.

Decorin is a small leucine-rich proteoglycan which is a component of the extracellular matrix of many connective tissues. We have developed a method for expression and purification of decorin as a fusion protein in Escherichia coli. A PCR product coding for the 330-amino-acid-residue secreted form of bovine decorin core protein was cloned into the vector pMal-c for expression in E. coli as a maltose-binding protein (MBP) fusion. Expressed MBP-decorin tended to form insoluble aggregates resistant to degradation by E. coli intracellular proteases. Fusion protein was therefore solubilized from bacterial inclusion bodies using guanidine HCl and refolded by dilution of the chaotrope to minimally denaturing conditions and disulfide shuffling. Final purification included amylose resin affinity chromatography and size exclusion chromatography. The 79-kDa MBP-decorin fusion protein could be completely cleaved by factor Xa protease in 24 h to yield 43-kDa MBP and 36-kDa decorin core protein. The decorin core protein was separated from MBP and factor Xa protease by DEAE-Sephacel chromatography. Using a solid-phase assay, we have characterized its binding affinity for extracellular matrix components known to interact with tissue-derived decorin including collagen type VI, collagen type I, and fibronectin. The purification and refolding protocol described here may be generally applicable to bacterial expression of other members of this growing family of related small leucine-rich proteoglycan core proteins.

ATP-Binding Cassette Transporters↗
PubMed2001

Expression of a decorin-like moleculein human melanoma.

Decorin, a member of the family of small leucin-rich proteoglycans, has originally been described as a secreted proteoglycan component of the connective tissues, and has been implicated in the negative regulation of cell proliferation directly or via interactions with TGF-beta. It was reported to be generally absent from tumor cells. Here we show that human melanoma cell lines express a decorin-like molecule. We detected decorin mRNA by RT-PCR in 7 out 7 human melanoma lines characterized by various metastatic potential. Using polyclonal antiserum against the core protein of decorin, the typical 80-120 kD glycanated form as well as a high molecular weight aberrant version (200-210 kD) of decorin were demonstrated by Western blot technique in the culture supernatants as well as in lysates of human melanoma cells. Finally, decorin epitope was also demonstrated immunohistochemically in human melanoma xenografts, as well as in tumor cells of surgically resected melanomas but not in melanocytes of nevi. The expression of this aberrant decorin did not inhibit the in vitroor in vivogrowth of human melanoma cells, and it was independent of their metastatic potential. Human melanoma cell lines expressing aberrant decorin retained sensitivity to the antiproliferative and gelatinase-stimulatory effects of exogenous TGF-beta.

Animals↗
PubMed1997

Effects of bone CS-proteoglycans, DS-decorin, and DS-biglycan on hydroxyapatite formation in a gelatin gel.

The small leucine-rich bone proteoglycans, biglycan and decorin, can be purified by chromatography on hydroxyapatite columns, demonstrating their potential affinities for bone apatite. To determine their effects on in vitro apatite formation and growth, a mixture of the chondroitin-sulfate (CS) bone proteoglycans, or purified fractions of the dermatan sulfate (DS) containing proteoglycans, DS-decorin and DS-biglycan obtained from skin and articular cartilage, respectively, were analyzed in a gelatin gel diffusion system in which apatite formation occurs in the absence of proteins in a 3.5 day period. Low concentrations of the bone CS-proteoglycan mixture and low DS-biglycan concentrations (5-25 microg/ml) increased apatite formation relative to proteoglycan-free controls at 3.5 days. The CS-proteoglycan mixture was less effective at 50 microg/ml than at 10 microg/ml. DS-biglycan was similarly most effective at 5-25 microg/ml. At 5 days, when apatite growth and proliferation were assessed, 10 and 50 microg/ml of both CS-bone proteoglycan and DS-biglycan increased mineral yields. DS-decorin, in contrast, had no significant effect on mineral accumulation at any of these concentrations. In seeded growth experiments, 1 and 10 microg/ml CS-proteoglycan and 10 and 50 microg/ml DS-biglycan were significant effective inhibitors of mineral accretion, whereas DS-decorin showed no tendency to inhibit seeded growth. Using molar extinction coefficients to determine concentrations, the binding of DS-biglycan and DS-decorin to apatite (specific surface 54 m2/g) was determined using a Langmuir adsorption isotherm model. DS-biglycan had a greater affinity for apatite than DS-decorin (0.285 ml/micromol versus 0.0098 ml/micromol). DS-biglycan binding was more specific with fewer binding sites (3.5 micromol/m2 compared with 18. 2 micromol/m2 for DS-decorin). Data suggest that of the small proteoglycans, biglycan may play a more significant role than decorin in the regulation of mineralization.

Animals↗