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The mechanism of scar reduction by copper peptides seems to revolve around the protein decorin. GHK-copper increases the production of decorin while suppressing the scar forming protein TGF-beta-1. Decorin has broad scar reduction properties and is able to bind to TGF-beta-1 and inactivate it. If decorin levels do not rise rapidly after an injury, then there is extensive scar formation.
Also decorin increases nerve and muscle regeneration plus has strong anti-cancer and anti-cancer metastases actions.
For more information, read the published abstracts below.
1. GHK-copper increases Decorin
J Invest Dermatol. 2000 Dec;115(6):962-8.
Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+).
Siméon A, Wegrowski Y, Bontemps Y, Maquart FX. Laboratoire de Biochimie Médicale et de Biologie Moléculaire, FRE CNRS 2260, IFR 53-Biomolécules, Faculté de Médecine, Reims, France.
Glycyl-histidyl-lysine-Cu(2+) is a tripeptide-copper complex previously shown to be an activator of wound healing. We have investigated the effects of glycyl-histidyl-lysine-Cu(2+) on the synthesis of glycosaminoglycans and small proteoglycans in a model of rat experimental wounds and in rat dermal fibroblast cultures. Repeated injections of glycyl-histidyl-lysine-Cu(2+) (2 mg per injection) stimulated the wound tissue production, as appreciated by dry weight and total protein measurements. This stimulation was accompanied by an increased production of type I collagen and glycosaminoglycans (assessed, respectively, by hydroxyproline and uronic acid contents of the chamber). Electrophoretic analysis of wound tissue glycosaminoglycans showed an accumulation of chondroitin sulfate and dermatan sulfate in control wound chambers, whereas the proportion of hyaluronic acid decreased with time. The accumulation of chondroitin sulfate and dermatan sulfate was enhanced by glycyl-histidyl-lysine-Cu(2+) treatment. The expression of two small proteoglycans of the dermis, decorin and biglycan, was analyzed by northern blot. The biglycan mRNA steady-state level in the chamber was maximal at day 12, whereas the decorin mRNA increased progressively until the end of the experiment (day 22). Glycyl-histidyl-lysine-Cu(2+) treatment increased the mRNA level of decorin and decreased those of biglycan. In dermal fibroblast cultures, the stimulation of decorin expression by glycyl-histidyl-lysine-Cu(2+) was also found. In contrast, biglycan expression was not modified. These results show that the expression of different proteoglycans in wound tissue are regulated in a different manner during wound healing. The glycyl-histidyl-lysine-Cu(2+) complex is able to modulate the expression of the extracellular matrix macromolecules differently during the wound repair process.
2. GHK-copper suppresses TGF-beta1
Arch Facial Plast Surg. 2001 Jan-Mar;3(1):28-32.
The effect of copper tripeptide and tretinoin on growth factor production in a serum-free fibroblast model.
McCormack MC, Nowak KC, Koch RJ.
Division of Otolaryngology-Head and Neck Surgery, Stanford University Medical Center, Stanford, Calif 94305-5328, USA.
OBJECTIVE: To evaluate the effect of copper tripeptide and tretinoin on normal and keloid-producing dermal fibroblasts in a serum-free in vitro model. The cellular response was described in terms of viability and secretion of basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1). METHODS: Primary cell lines were established from patient facial skin samples obtained during surgery and plated in serum-free media. At 0 hour, copper tripeptide (1 x 10 (-9) mol/L), tretinoin (1 x 10 (-5) mol/L), or appropriate control vehicle was added. Cell counts and viability were established at 24, 72, and 120 hours. Supernatants were collected at the same intervals and were assessed for bFGF and TGF-beta1 concentrations using the enzyme-linked immunosorbent assay technique. RESULTS: Cell lines showed viability between 86% and 96% (mean, 92%) throughout the experiment. Tretinoin-treated normal fibroblasts secreted more bFGF than did controls at 24 hours (P<.05). Tretinoin-treated keloid-producing fibroblasts secreted more TGF-beta1 than did controls at 120 hours (P<.05). Keloid-producing fibroblasts treated with copper tripeptide secreted less TGF-beta1 than did controls at 24 hours (P<.05); a similar trend was observed in normal fibroblasts. CONCLUSIONS: Normal fibroblasts treated with tretinoin produced more bFGF than did controls, and this might partially explain the clinically observed tightening effects of tretinoin. Normal and keloid-producing dermal fibroblasts treated with copper tripeptide secreted less TGF-beta1 than did controls, suggesting a possible clinical use for decreasing excessive scar formation.
3. Decorin, Scars and Fibrosis
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Note: The next abstract is typical of many such observations. Initial low decorin seems to be the trigger for
fibrosis and heavy scars.
Histopathology. 2000 Mar;36(3):262-72.
Delayed appearance of decorin in healing burn scars.
Sayani K, Dodd CM, Nedelec B, Shen YJ, Ghahary A, Tredget EE, Scott PG.
Division of Plastic Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
AIMS: We have previously shown that hypertrophic scar tissue from burn patients contains abnormally high amounts of the proteoglycans versican and biglycan and reduced amounts of decorin, in comparison with normal dermis or mature scar. The lack of decorin may account for the poor organization of collagen fibrils in the nodular areas of these scars. Decorin has also been reported to neutralize the fibrogenic growth factor TGF-beta1. This study was conducted to monitor the time-course of expression of decorin in healing burn wounds by in-situ hybridization to determine whether its absence from hypertrophic scars could result from reduced synthesis. METHODS AND RESULTS: Scar tissue from 19 patients and normal dermis from six patients, was fixed in paraformaldehyde, embedded in paraffin and sectioned. Digoxigenin-labelled cRNA probes were prepared from a plasmid containing a 622-bp insert of human decorin cDNA and used for in-situ hybridization. Total numbers of connective tissue cells and cells positive for decorin mRNA were counted in 10 random fields in the upper (papillary), middle and lower (reticular) one-thirds of the dermis. In all regions the number and percentages of cells with decorin mRNA were low during the first 12 months after injury (eight samples), much higher between 12 and 36 months (seven samples) and low and similar to those in normal skin after 36 months (five samples). The differences between intermediate and early or late stage samples were statistically significant (one-way ANOVA). Immunohistochemistry showed little staining for decorin in early stage samples and much stronger staining in mid-stage. Late stage tissue showed intense staining for decorin, almost comparable to that in normal dermis. CONCLUSION: Expression of decorin in burn wounds is suppressed for about 12 months and then increases at a time when resolution of hypertrophic scarring is generally considered to occur.
Nature. 1992 Nov 26;360(6402):361-4.
Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease.
Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E.
Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132.
The central pathological feature of human kidney disease that leads to kidney failure is the accumulation of extracellular matrix in glomeruli. Overexpression of transforming growth factor-beta (TGF-beta) underlies the accumulation of pathological matrix in experimental glomerulonephritis. Administration of an antibody raised against TGF-beta to glomerulonephritic rats suppresses glomerular matrix production and prevents matrix accumulation in the injured glomeruli. One of the matrix components induced by TGF-beta, the proteoglycan decorin, can bind TGF-beta and neutralize its biological activity, so decorin may be a natural regulator of TGF-beta (refs 3, 4). We tested whether decorin could antagonize the action of TGF-beta in vivo using the experimental glomerulonephritis model. We report here that administration of decorin inhibits the increased production of extracellular matrix and attenuates manifestations of disease, confirming our hypothesis. On the basis of our results, decorin may eventually prove to be clinically useful in diseases associated with overproduction of TGF-beta.
Exp Neurol. 1999 Oct;159(2):504-10.
Decorin attenuates gliotic scar formation in the rat cerebral hemisphere.
Logan A, Baird A, Berry M.
Department of Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous CNS pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aimed to demonstrate significant inhibition of fibrogenesis, glial scarring, and inflammation in penetrating incisional wounds of the rat brain using the proteoglycan decorin, which effectively inhibits TGF-beta activity. Adult rats were assigned to two treatment groups each receiving 14 daily intraventricular injections of 10 microliter total volume of: (i) saline plus 0.3% autologous rat serum = 30 microgram protein); or (ii) saline plus 30 microgram recombinant human decorin. On day 0 of the experiment, a stereotactically defined unilateral incisional lesion was placed through the cerebral cortex into the lateral ventricle and, after 14 days, brains were processed for immunohistochemical analysis of the lesion site. Specific antibodies were used to visualize the deposition within the wound of matrix molecules and the extent and nature of reactive astrocytosis and inflammation. Quantitative and qualitative image analysis of the fibrous scar was performed in sections from a defined anatomical plane through the wound to detect the antifibrotic effects of decorin treatment. Treatment of wounds with decorin led to a marked attenuation of all aspects of CNS scarring including matrix deposition, formation of an accessory glial limiting membrane, and inflammation. Our findings suggest that decorin is potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components and maintain and/or restore functional integrity
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J Orthop Res. 2001 May;19(3):456-62. Suppression of fibrous adhesion by proteoglycan decorin. Fukui N, Fukuda A, Kojima K, Nakajima K, Oda H, Nakamura K. Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Japan. fukuin@msnotes.wustl.edu
Small proteoglycan decorin is known to suppress the bioactivity of TGF-beta through a competitive binding with the cell surface receptors for the cytokine. Based on this knowledge, we hypothesized that decorin could reduce the formation of fibrous adhesion, because our previous study showed the neutralizing antibody to TGF-beta1 has that effect. An intra-articular adhesion model in the rabbit knee joint was employed in this study, and decorin was administered into the joint cavity continuously during the 4 weeks of the experiment. The results of the dose-response study demonstrated that decorin suppresses formation of fibrous adhesion in a dose-dependent manner. When the administration of decorin was limited to shorter periods, this effect was considerably impaired and the necessity of long-term administration was demonstrated. On the other hand, when administered together with TGF-beta1, decorin still suppressed adhesion but to a lesser extent, and it was suggested that this proteoglycan could have other significant mechanism(s) to suppress adhesion besides the neutralization of TGF-beta. Thus, the present study showed that decorin could inhibit adhesion formation by both TGF-beta dependent and independent mechanisms. Considering that decorin exists ubiquitously in the body, its administration might be a promising approach to suppress adhesion.
Am J Sports Med. 2001 Jul-Aug;29(4):394-402.
The use of an antifibrosis agent to improve muscle recovery after laceration.
Fukushima K, Badlani N, Usas A, Riano F, Fu F, Huard J.
Department of Orthopaedic Surgery, Children's Hospital of Pittsburgh and University of Pittsburgh, Pennsylvania 15213, USA.
Muscle injuries are challenging problems in traumatology and the most frequent injuries in sports medicine. Muscle injuries are capable of healing, although slowly and occasionally with incomplete functional recovery. We observed that lacerated muscle undergoes a rapid process of regeneration, which is hindered by the development of fibrosis. Biologic approaches to enhance muscle regeneration and prevent fibrosis are being investigated to improve muscle healing after injuries. We observed that growth factors can improve muscle regeneration but cannot prevent muscle fibrosis. We investigated the use of an antifibrosis substance, decorin, as an approach to prevent fibrosis and thereby improve muscle healing after injury in murine muscle. We observed that direct injection of human recombinant decorin can efficiently prevent fibrosis and enhance muscle regeneration in the lacerated muscle. More importantly, decorin can improve the recovery of strength in the injured muscle to a level similar to that observed in normal noninjured muscle. These results suggest that injection of decorin improves both the muscle structure and the function of the lacerated muscle to near complete recovery. This study will contribute significantly to the development of strategies to promote efficient muscle healing and complete functional recovery after muscle injuries
J Orthop Res. 2003 Sep;21(5):798-804.
Gamma interferon as an antifibrosis agent in skeletal muscle.
Foster W, Li Y, Usas A, Somogyi G, Huard J.
Growth and Development Laboratory, Department of Orthopaedic Surgery, 4151 Rangos Research Center, Children's Hospital of Pittsburgh and University of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583, USA.
Muscle injuries are a common problem in sports medicine. Skeletal muscle can regenerate itself, but the process is both slow and incomplete. Previously we and others have used growth factors to improve the regeneration of muscle, but the muscle healing was impeded by scar tissue formation. However, when we blocked the fibrosis process with decorin, an antifibrosis agent, we improved the muscle healing. Here we show that gammainterferon (gammaINF)--a cytokine that inhibits the signaling of transforming growth factor beta1 (TGFbeta1), a fibrotic stimulator--reduces fibrosis formation and improves the healing of lacerated skeletal muscle. With gammaINF treatment, the growth rate of muscle-derived fibroblasts was reduced and the level of fibrotic protein expression induced by TGFbeta1 (including TGFbeta1, vimentin, and alpha-smooth muscle actin) was down-regulated in vitro. In a mouse laceration model, the area of fibrosis decreased when gammaINF was injected at either 1 or 2 weeks after injury. More importantly, the injection of gammaINF at either 1 or 2 weeks post-injury was found to improve muscle function in terms of both fast-twitch and tetanic strength. This study demonstrates that gammaINF is a potent antifibrosis agent that can improve muscle healing after laceration injury.
Am J Pathol. 2004 Mar;164(3):1007-19. Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Growth and Development Laboratory, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213-2583, USA. jhuard+@pitt.edu
Transforming growth factor-beta1 (TGF-beta1) is thought to play a crucial role in fibrotic diseases. This study demonstrates for the first time that TGF-beta1 stimulation can induce myoblasts (C2C12 cells) to express TGF-beta1 in an autocrine manner, down-regulate the expression of myogenic proteins, and initiate the production of fibrosis-related proteins in vitro. Direct injection of human recombinant TGF-beta1 into skeletal muscle in vivo stimulated myogenic cells, including myofibers, to express TGF-beta1 and induced scar tissue formation within the injected area. We also observed the local expression of this growth factor by myogenic cells, including regenerating myofibers, in injured skeletal muscle. Finally, we demonstrated that TGF-beta1 gene-transfected myoblasts (CT cells) can differentiate into myofibroblastic cells after intramuscular transplantation, but that decorin, an anti-fibrosis agent, prevents this differentiation process by blocking TGF-beta1. In summary, these findings indicate that TGF-beta1 is a major stimulator that plays a significant role in both the initiation of fibrotic cascades in skeletal muscle and the induction of myogenic cells to differentiate into myofibroblastic cells in injured muscle
Invest Ophthalmol Vis Sci. 2005 Jan;46(1):191-6. Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study. Grisanti S, Szurman P, Warga M, Kaczmarek R, Ziemssen F, Tatar O, Bartz-Schmidt KU. Department of Ophthalmology, Eberhard-Karls University Tübingen, Tübingen, Germany. salvatore.grisanti@med.uni-tuebingen.de
PURPOSE: To analyze the effect of perioperative decorin in an experimental setting of glaucoma filtration surgery. METHODS: Glaucoma filtration surgery, similar to that performed in clinical practice, was performed on 35 chinchilla rabbits (ChBB:CH). The animals received a unilateral subconjunctival injection of decorin (40-100 microg) or the vehicle alone before surgery and at different time intervals thereafter. Antifibrotic efficacy was established by clinical response and histologic examination. The animals were killed on day 14, and the eyes processed for histology. RESULTS: Both the vehicle and the decorin solution were well tolerated. No adverse effects such as inflammation or blurring of the optical media were observed. Conjunctival scarification occurred within 1 week in the control groups but was suppressed in the experimental groups. The intraocular pressure correlated with the fibrotic process and reached normal levels within 7 days after surgery in control animals, but remained significantly (P <0.001) reduced in the experimental groups. Histologic examination of the surgical area 14 days after surgery disclosed massive fibrosis in the control animals, but little deposition of extracellular matrix in the experimental groups. CONCLUSIONS: The data of this pilot study suggest that perioperative subconjunctival decorin applications significantly affect conjunctival scarring and surgical outcome of glaucoma filtration treatments in rabbits.
Matrix Biol. 2005 Jun;24(4):313-24.
A role for decorin in the remodeling of myocardial infarction.
Weis SM, Zimmerman SD, Shah M, Covell JW, Omens JH, Ross J Jr, Dalton N, Jones Y, Reed CC, Iozzo RV, McCulloch AD.
Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA 92093, USA. sweis@ucsd.edu
Because the small leucine-rich proteoglycan decorin has been implicated in regulation of collagen fibrillogenesis leading to proper extracellular matrix assembly, we hypothesized it could play a key role in cardiac fibrosis following myocardial infarction. In this study we ligated the left anterior descending coronary artery in wildtype and decorin-null mice to produce large infarcts in the anterior wall of the left ventricle. At early stages post-coronary occlusion the myocardial infarction size did not appreciably differ between the two genotypes. However, we found a wider distribution of collagen fibril sizes with less organization and loose packing in mature scar from decorin-null mice. Thus, we tested the hypothesis that these abnormal collagen fibrils would adversely affect post-infarction mechanics and ventricular remodeling. Indeed, scar size, right ventricular remote hypertrophy, and left ventricular dilatation were greater in decorin-null animals compared with wildtype littermates 14 days after acute myocardial infarction. Echocardiography revealed depressed left ventricular systolic function between 4 and 8 weeks post-ischemia in the decorin-null animals. These changes indicate that decorin is required for the proper fibrotic evolution of myocardial infarctions, and that its absence leads to abnormal scar tissue formation. This might contribute to aneurysmal ventricular dilatation, remote hypertrophy, and depressed ventricular function.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007 Feb;24(1):222-5.
[The action of decorin in anti-fibrosis and anti-cancer]
[Article in Chinese]
Ma W, Tan Y, Cai S, Chen H, Du J, Cai S.
Key Laboratory for Biomechanics & Tissue Engineering of the State Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity.
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Burns. 2009 Jun;35(4):527-37. Epub 2009 Jan 23.
Recombinant human decorin inhibits TGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts.
Zhang Z, Garron TM, Li XJ, Liu Y, Zhang X, Li YY, Xu WS.
Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China. zhangzhicc48@163.com
Decorin was reported to bind transforming growth factor-beta (TGF-beta(1)) and neutralise some of its activity as a key regulator of wound contraction and hypertrophic scar formation. In this study, we investigated whether recombinant human decorin affected TGF-beta(1)-induced fibroblast contractile activity, by using fibroblast-populated collagen lattice with decorin added to the collagen gel. Hypertrophic scar fibroblasts showed greater basal contraction of collagen gels than normal fibroblasts, and the addition of TGF-beta(1) significantly enhanced this. Decorin inhibited both the basal and TGF-beta(1)-enhanced contraction of collagen gel by both normal and hypertrophic scar fibroblasts. Decorin also inhibited TGF-beta(1)-induced alpha-smooth muscle actin (alpha-SMA), plasminogen activator inhibitor-1 (PAI-1) protein and mRNA expressions in normal and hypertrophic scar fibroblasts. These results suggest that decorin may have therapeutic potential for excessive skin contraction as observed in hypertrophic scarring.
Burns. 2007 Aug;33(5):634-41. Epub 2007 Mar 19.
Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts.
Zhang Z, Li XJ, Liu Y, Zhang X, Li YY, Xu WS.
Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, PR China. zhangzhicc48@163.com
Hypertrophic scarring remains a major problem for patients who have suffered deep burns. The pathophysiology underlying hypertrophic scar formation may be driven by the biological activity of transforming growth factor beta1 (TGF-beta(1)). Decorin is a human proteoglycan that inactivates the effect of TGF-beta(1) and therefore displays a beneficial effect of antifibrosis in various tissues. Hypertrophic scarring is a fibroproliferative disorder of the dermis that occurs following wounding. This study investigated the effects of decorin on cell proliferation, TGF-beta(1) production, and collagen synthesis in hypertrophic scar fibroblasts. The cell proliferation rates, cell cycle distribution, low-molecular-weight apoptotic DNA and TGF-beta(1) levels, and contents of type I and type III collagen amino-terminal propeptide (PINP, PIIINP) in supernatants were assessed. Fibroblast proliferation was significantly (P<0.05) inhibited by decorin, and this effect was dose-dependent. The fibroblast population became stationary at decorin concentrations of 100 and 200 nM. Decorin inhibited fibroblast proliferation by inducing cell growth arrest but not apoptosis. TGF-beta(1) and PINP levels were significantly (P<0.05) lower in fibroblasts treated with 10, 50, 100, 200 nM of decorin compared with fibroblasts without decorin addition. However, there was no significant difference in PIIINP concentration between the decorin-treated group and the control group. These results suggest that decorin has a down-regulatory effect on cell proliferation, TGF-beta(1) production, and collagen synthesis in hypertrophic scar fibroblasts. Improved understanding of such a regulatory mechanisms may eventually be of therapeutic significance in the control of hypertrophic scarring.
4. Nerve Regeneration
Eur J Neurosci. 2004 Mar;19(5):1226-42.
Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries.
Davies JE, Tang X, Denning JW, Archibald SJ, Davies SJ.
Department of Neurosurgery, Baylor College of Medicine, Scurlock Tower Suite 944, 6560 Fannin Street, Houston, TX 77030, USA.
The formation of misaligned scar tissue by a variety of cell types expressing multiple axon growth inhibitory proteoglycans presents a physical and molecular barrier to axon regeneration after adult spinal cord injuries. Decorin is a small, leucine-rich proteoglycan that has previously been shown to reduce astrogliosis and basal lamina formation in acute cerebral cortex stab injuries. We have therefore tested whether mini pump infusion of hr-decorin into acute stab injuries of the adult rat spinal cord can not only inhibit formation of an astroglial limitans but also deposition of the axon growth inhibitory proteoglycans neurocan, NG2, phosphacan and brevican. Combined immunohistochemical and quantitative Western blot analysis revealed major reductions in levels of core protein expression (>80% for 130-kDa neurocan, 145/80-kDa brevican, 300-kDa phosphacan) and immunoreactivity for all four chondroitin sulfate proteoglycans (CSPGs) within decorin-treated injuries compared with untreated controls. Astrogliosis within lesion margins and the accumulation of OX42+ macrophages/microglia within lesion centres were also significantly reduced. These decorin-induced changes in scar formation combined to promote the striking ability of axons from microtransplanted adult sensory neurons to enter, grow within and exit decorin-infused spinal cord injuries, in sharp contrast to the complete failure of axons to cross untreated, CSPG-rich lesions. Decorin pretreatment of meningial fibroblasts in vitro also resulted in a three-fold increase in neurite outgrowth from co-cultured adult sensory neurons and suppression of NG2 immunoreactivity. The ability of decorin to promote axon growth across acute spinal cord injuries via a coordinated suppression of inflammation, CSPG expression and astroglial scar formation make decorin treatment a promising component of future spinal cord regeneration strategies.
Congenit Anom (Kyoto). 2004 Dec;44(4):181-8.
Proteoglycans and injury of the central nervous system.
Matsui F, Oohira A.
Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan. fmatsui@inst-hsc.jp.
Proteoglycan is a family of glycoproteins which carry covalently-linked glycosaminoglycan chains, such as chondroitin sulfate and heparan sulfate. Proteoglycans are believed to play important roles in morphogenesis and maintenance of various tissues including the central nervous system (CNS) through interactions with cell adhesion molecules and growth factors. In the CNS, a significant amount of evidence has been accumulated to show that proteoglycans function as modulators in various cellular events not only in the development, but also in the pathogenesis of neuronal diseases and lesions. When the CNS is injured, several chondroitin sulfate proteoglycans (CSPG) are up-regulated in glial scars formed around the lesion site. The glial scar also contains some molecules inhibitory to axonal growth, such as myelin-associated glycoprotein, Nogo, and Semaphorin. In vitro studies revealed that CSPG largely exert a repulsive effect on axonal regeneration, and a signal from CSPG modulates the actin cytoskeleton of outgrowing neurites through the Rho/ROCK pathway. These findings suggest that CSPG are responsible for unsuccessful axonal regeneration in glial scars. Various attempts to overcome the inhibitory effect of CSPG have been pursued in vivo. Digestion of chondroitin sulfate chains by chondroitinase ABC, suppression of CSPG core protein synthesis by decorin, suppression of glycosaminoglycan chain synthesis by a DNA enzyme, and inhibition of the Rho/ROCK pathway with specific inhibitors were all successful for increasing axonal regeneration. For a clinical application, the most effective combination of these treatments needs to be examined in the future.
Eur J Neurosci. 2004 Mar;19(5):1226-42.
Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries.
Davies JE, Tang X, Denning JW, Archibald SJ, Davies SJ.
Department of Neurosurgery, Baylor College of Medicine, Scurlock Tower Suite 944, 6560 Fannin Street, Houston, TX 77030, USA.
The formation of misaligned scar tissue by a variety of cell types expressing multiple axon growth inhibitory proteoglycans presents a physical and molecular barrier to axon regeneration after adult spinal cord injuries. Decorin is a small, leucine-rich proteoglycan that has previously been shown to reduce astrogliosis and basal lamina formation in acute cerebral cortex stab injuries. We have therefore tested whether mini pump infusion of hr-decorin into acute stab injuries of the adult rat spinal cord can not only inhibit formation of an astroglial limitans but also deposition of the axon growth inhibitory proteoglycans neurocan, NG2, phosphacan and brevican. Combined immunohistochemical and quantitative Western blot analysis revealed major reductions in levels of core protein expression (>80% for 130-kDa neurocan, 145/80-kDa brevican, 300-kDa phosphacan) and immunoreactivity for all four chondroitin sulfate proteoglycans (CSPGs) within decorin-treated injuries compared with untreated controls. Astrogliosis within lesion margins and the accumulation of OX42+ macrophages/microglia within lesion centres were also significantly reduced. These decorin-induced changes in scar formation combined to promote the striking ability of axons from microtransplanted adult sensory neurons to enter, grow within and exit decorin-infused spinal cord injuries, in sharp contrast to the complete failure of axons to cross untreated, CSPG-rich lesions. Decorin pretreatment of meningial fibroblasts in vitro also resulted in a three-fold increase in neurite outgrowth from co-cultured adult sensory neurons and suppression of NG2 immunoreactivity. The ability of decorin to promote axon growth across acute spinal cord injuries via a coordinated suppression of inflammation, CSPG expression and astroglial scar formation make decorin treatment a promising component of future spinal cord regeneration strategies.
Neurobiol Dis. 2008 Oct;32(1):88-95. Epub 2008 Jun 26.
Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons.
Minor K, Tang X, Kahrilas G, Archibald SJ, Davies JE, Davies SJ.
Department of Neurosurgery, Anschutz Medical Campus, University of Colorado at Denver, Neurosurgery Research Laboratory, Aurora, CO 80045, USA.
Inhibitory chondroitin sulfate proteoglycans (CSPGs) and myelin-associated molecules are major impediments to axon regeneration within the adult central nervous system (CNS). Decorin infusion can however suppress the levels of multiple inhibitory CSPGs and promote axon growth across spinal cord injuries [Davies, J.E., Tang, X., Denning, J.W., Archibald, S.J., and Davies, S.J., 2004. Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur. J. Neurosci. 19, 1226-1242]. A question remained as to whether decorin can also increase axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. We have therefore conducted an in vitro analysis of neurite extension by decorin-treated adult dorsal root ganglion (DRG) neurons cultured on substrates of inhibitory CSPGs or myelin membranes mixed with laminin. Decorin treatment promoted 14.5 and 5-fold increases in average neurite length/neuron over untreated controls on CSPGs or myelin membranes respectively. In addition to suppressing inhibitory scar formation, our present data shows that decorin can directly boost the ability of neurons to extend axons within CSPG or myelin rich environments.
J Neurotrauma. 2006 Mar-Apr;23(3-4):397-408.
Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro.
Davies JE, Tang X, Bournat JC, Davies SJ.
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Spinal cord scar tissue presents a combined physical and molecular barrier to axon regeneration. Theoretically, spinal cord injuries (SCIs) can be rendered more permissive to axon growth by either suppressing synthesis of misaligned, fibrotic scar tissue and associated axon growth inhibitors, or enzymatically degrading them. We have previously shown that acute infusion of human recombinant decorin core protein into discreet stab injuries of the rat dorsal column pathways effected a major suppression of inflammation, astrogliosis, and multiple axon growth inhibitory chondroitin sulfate proteoglycans, which combined to promote rapid axon growth across the injury site. The high efficiency of chondroitin sulfate proteoglycan (CSPG) core protein suppression (approximately 90%) suggested that decorin may promote CSPG degradation in addition to suppressing CSPG synthesis. As the serine protease plasmin can degrade axon growth inhibitory CSPGs (neurocan and phosphacan) and its zymogen, plasmininogen is synthesized by microglia, we have investigated whether decorin treatment of acute SCIs and cultured adult spinal cord microglia can increase plasminogen/ plasmin synthesis. Infusion of hr-decorin over the first 8 days post-SCI induced 10- and 17-fold increases in plasminogen and plasmin protein levels, respectively, within sites of injury and a threefold increase in microglial plasminogen mRNA in vitro. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting central nervous system (CNS) plasticity. The wider implications of decorin induction of plasmin in the injured spinal cord for axon regeneration, and recovery of function at acute and chronic time points post-SCI are reviewed.
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5. Muscle Regeneration
Mol Ther. 2007 Sep;15(9):1616-22. Epub 2007 Jul 3.
Decorin gene transfer promotes muscle cell differentiation and muscle regeneration.
Li Y, Li J, Zhu J, Sun B, Branca M, Tang Y, Foster W, Xiao X, Huard J.
Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
We have shown that decorin, a small leucine-rich proteoglycan, can inhibit transforming growth factor (TGF)-beta1 to prevent fibrous scar formation and improve muscle healing after injury. In the decorin-treated muscle, an enhancement of muscle regeneration is observed through histological examination. In this article, we report our determination of whether decorin has a direct effect on myogenic cells' differentiation. Our results indicate that myoblasts genetically engineered to express decorin (CD cells) differentiated into myotubes at a significantly higher rate than did control myoblasts (C2C12). This enhanced differentiation led to the up-regulation of myogenic genes (Myf5, Myf6, MyoD, and myogenin) in CD cells in vitro. We speculate that the higher rate of differentiation exhibited by the CD cells is due to the up-regulation of follistatin, peroxisome-proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha), p21, and the myogenic genes, and the down-regulation of TGF-beta1 and myostatin. Decorin gene transfer in vivo promoted skeletal muscle regeneration and accelerated muscle healing after in. These results suggest that decorin not only prevents fibrosis but also improves muscle regeneration and repair.
6. Anti-Cancer Actions
Oncogene. 2005 Feb 3;24(6):1104-10.
Decorin prevents metastatic spreading of breast cancer.
Reed CC, Waterhouse A, Kirby S, Kay P, Owens RT, McQuillan DJ, Iozzo RV.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Metastases in breast cancer are a vital concern in treatment, with epidermal growth factor receptor and ErbB2 strongly implicated in mediating tumor invasion and spreading. In this study, we investigated the role of decorin in suppressing both primary breast carcinomas and pulmonary metastases. We show that decorin causes marked growth suppression both in vitro and in vivo using a metastatic breast cancer cell line and an orthotopic mammary carcinoma model. Treatment with decorin protein core reduced primary tumor growth by 70% and eliminated observed metastases. An adenoviral vector containing the decorin transgene caused primary tumor retardation of 70%, in addition to greatly reducing observed metastases. Moreover, we demonstrate that ErbB2 phosphorylation and total receptor protein levels are reduced in this model system upon de novo expression of decorin under the control of a doxycycline-inducible promoter. Primary tumor growth in vivo was reduced by up to 67% upon decorin induction, and pulmonary metastases were markedly hampered as well. These effects are likely occurring through decorin's long-term downregulation of the ErbB2 tyrosine kinase cascade. These results demonstrate a novel role for decorin in reduction or prevention of tumor metastases in this breast cancer model and could eventually lead to improved therapeutics for metastatic breast cancer.
Oncol Rep. 2008 Jun;19(6):1533-9.
Decorin suppresses lung metastases of murine osteosarcoma.
Shintani K, Matsumine A, Kusuzaki K, Morikawa J, Matsubara T, Wakabayashi T, Araki K, Satonaka H, Wakabayashi H, Iino T, Uchida A.
Department of Orthopaedic Surgery, Mie University Faculty of Medicine, Mie, Japan.
Lung metastasis is the most crucial event affecting the therapeutic outcome of osteosarcoma. The prevention of lung metastasis is therefore important in improving the prognosis of patients with osteosarcoma. Decorin is a major extracellular matrix protein which has become the focus of various cancer studies. The biological role of decorin in osteosarcoma has yet to be clarified. The aim of this study was to examine the potential of decorin as a novel biological target for the treatment of osteosarcoma. In this study, the LM8 murine osteosarcoma cell line (LM8) with high metastatic potential to the lung was used. The two cell lines established were LM8-DCN which stably expressed human decorin (hDCN) and LM8-mock, established as a control. The LM8-DCN cell line was subcutaneously injected into the backs of mice. Significantly fewer pulmonary metastases were observed in mice with LM8-DCN compared to mice inoculated with LM8 and LM8-mock (P<0.001). In addition, the mice in the LM8-DCN inoculated group survived significantly longer than those in the LM8 and LM8-mock inoculated group, based on the Kaplan-Meier survival analysis and log-rank tests (P<0.005). The effect of decorin on the growth rates, motility and invasion ability of LM8 was investigated in vitro. There was no difference in the morphology and growth rates, but the motility and invasion of LM8 were inhibited by decorin. These results suggest that decorin has the therapeutic potential to prevent lung metastasis in osteosarcoma.
Am J Pathol. 2008 Sep;173(3):844-55. Epub 2008 Aug 7.
An antimetastatic role for decorin in breast cancer.
Goldoni S, Seidler DG, Heath J, Fassan M, Baffa R, Thakur ML, Owens RT, McQuillan DJ, Iozzo RV.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly, systemic delivery of decorin prevented metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative assays. In contrast, AG879 failed to have any effect. Our data support a role for decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.
Int J Cancer. 2008 Dec 1;123(11):2473-9.
Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs.
Goldoni S, Iozzo RV.
Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Decorin, the prototype member of the small leucine-rich proteoglycans, resides in the tumor microenvironment and affects the biology of various types of cancer by downregulating the activity of several receptors involved in cell growth and survival. Decorin binds to and modulates the signaling of the epidermal growth factor receptor and other members of the ErbB family of receptor tyrosine kinases. It exerts its antitumor activity by a dual mechanism: via inhibition of these key receptors through their physical downregulation coupled with attenuation of their signaling, and by binding to and sequestering TGFbeta. Decorin also modulates the insulin-like growth factor receptor and the low-density lipoprotein receptor-related protein 1, which indirectly affects the TGFbeta receptor pathway. When expressed in tumor xenograft-bearing mice or injected systemically, decorin inhibits both primary tumor growth and metastatic spreading. In this review, we summarize the latest reports on decorin and related molecules that are relevant to cancer and bring forward the idea of decorin as an anticancer therapeutic and possible prognostic marker for patients affected by various types of tumors. We also discuss the role of lumican and LRIG1, a novel cell growth inhibitor homologous to decorin.
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Oncology. 2009;77(2):92-9. Epub 2009 Jul 7.
Decorin suppresses bone metastasis in a breast cancer cell line.
Araki K, Wakabayashi H, Shintani K, Morikawa J, Matsumine A, Kusuzaki K, Sudo A, Uchida A. Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
Decorin, the prototype of an expanding family of small leucine-rich proteoglycans, is involved in a number of cellular processes including matrix assembly, fibrillogenesis and the control of cell proliferation. In this study, we investigated the role of decorin in suppressing tumor aggressiveness and bone metastases. We used a metastatic breast cancer cell line, MDA-MB-231, to show that decorin causes marked growth suppression bothin vitro and in vivo. A cytomegaloviral vector containing the decorin transgene caused greatly reduced cell growth, motility and observed metastases. Bone metastases were decreased by >90% upon decorin transfection. These results demonstrate a novel role for decorin in the reduction or prevention of tumor metastases in this breast cancer model and could eventually lead to improved therapies for metastatic breast cancer.
Neoplasia. 2009 Oct;11(10):1042-53.
Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways.
Hu Y, Sun H, Owens RT, Wu J, Chen YQ, Berquin IM, Perry D, O'Flaherty JT, Edwards IJ.
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Epidermal growth factor receptor (EGFR) and androgen receptor (AR) pathways play pivotal roles in prostate cancer progression. Therefore, agents with dual-targeting ability may have important therapeutic potential. Decorin, a proteoglycan present in the tumor microenvironment, is known to regulate matrix assembly, growth factor binding, and receptor tyrosine kinase activity. Here, we show that in prostate-specific Pten(P-/-) mice, a genetically defined, immune-competent mouse model of prostate cancer, systemic delivery of decorin inhibits tumor progression by targeting cell proliferation and survival pathways. Moreover, in human prostate cancer cells, we show that decorin specifically inhibits EGFR and AR phosphorylation and cross talk between these pathways. This prevents AR nuclear translocation and inhibits the production of prostate specific antigen. Further, the phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathway is suppressed leading to tumor cell apoptosis. Those findings highlight the effectiveness of decorin in the presence of a powerful genetic cancer risk and implicate decorin as a potential new agent for prostate cancer therapy by targeting EGFR/AR-PI3K-Akt pathways.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007 Feb;24(1):222-5.
[The action of decorin in anti-fibrosis and anti-cancer]
[Article in Chinese] Ma W, Tan Y, Cai S, Chen H, Du J, Cai S.
Key Laboratory for Biomechanics & Tissue Engineering of the State Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity.
Comment: Gly-His-Lys may suppress colorectal cancer Clin Exp Metastasis. 2010 Feb 9. [Epub ahead of print] A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Hong Y, Downey T, Eu KW, Koh PK, Cheah PY. Department of Colorectal Surgery, Singapore General Hospital, Singapore, 169608, Singapore. Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC. |
