Decorin treatment of spinal cord injury

Maryam Esmaeili, Martin Berry, Ann Logan, Zubair Ahmed

Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, UK

Decorin treatment of spinal cord injury

Maryam Esmaeili, Martin Berry, Ann Logan, Zubair Ahmed

Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, UK

The scarring response after a penetrant central nervous system injury results from the interaction between invading leptominingeal/pericyte-derived fi broblasts and endogenous reactive astrocytes about the wound margin. Extracellular matrix and scar-derived axon growth inhibitory molecules fi ll the lesion site providing both a physical and chemical barrier to regenerating axons. Dec orin, a small leucine-rich chondroitin-dermatan sulphate proteoglycan expressed by neurons and astrocytes in the central nervous system, is both anti- fi brotic and anti-in fl ammatory and attenuates the formation and partial dissolution of established and chronic scars. Here, we discuss the potential of using Decorin to antagonise scarring in the central nervous system.

spinal cord injury; Decorin; transforming growth factor-beta; scarring; chondroitin sulphate proteoglycan; matrix metalloproteases

Funding:This work was supported by the Wellcome Trust, grant No. 092539/Z/10/Z and the International Spinal Research Trust, grant No. STR103. AL is also funded by the National Institute for Health research (NIHR) Surgical Reconstruction and Microbiology Research Centre (partnership between University Hospitals Birmingham NHS Foundation Trust, the University of Birmingham and the Royal Centre for Defence Medicine).

Esmaeili M, Berry M, Logan A, Ahmed Z. Decorin treatment of spinal cord injury. Neural Regen Res. 2014;9(18)：1653-1656.

Introduction

The scarring that occurs after penetrant central nervous system (CNS) injury results from interaction between invading leptomeningeal/pericyte-derived fibroblasts and endogenous reactive astrocytes in the wound margins. The extracellular matrix (ECM) deposited in the lesion core by fi broblasts becomes sequestered from the surrounding neuropil by a laminin-rich basement membrane (glia limitansaccessoria-GLA) formed at the astrocyte/ fi broblast interface through the interaction of astrocyte-derived ephrins and eph-receptors on core fibroblasts (Bundesen et al., 2003). The environment in and around the developing CNS scar is rich in axon growth inhibitory chondroitin sulphate proteoglycans (CSPG), including neurocan, phosphacan, brevican and NG2 (Davies et al., 2004), semaphorin3A (Sema3A) and ephrin B3 (Sandvig et al., 2004), secreted by reactive endogenous astrocytes, oligodendrocyte progenitor cells (synantocytes) and also by immigrated core meningeal/pericyte-derived fi broblasts and leucocytes (Fitch and Silver, 1997; Fawcett and Asher, 1999; Sandvig et al., 2004; Kundi et al., 2013; Cregg et al., 2014). The CNS myelin-derived inhibitory Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte-derived myelin glycoprotein (OMgp) are also released into the peri-lesion neuropil as myelin is degraded (Fawcett and Asher, 1999; Sandvig et al., 2004; Berry et al., 2008; Minor et al., 2008; Kundi et al., 2013; Mei et al., 2013; Ahmed et al., 2014). Binding of these ligands to their respective cognate receptors activates the Rho/ROCK signalling pathway (required for the integrity of growth dynamics) and leads to growth cone collapse and arrest of CNS axon growth.

Fibrogenic growth factors and CNS scarring

Wound healing is orchestrated by many growth factors and cytokines prominent among which are transforming growth factor beta 1 and 2 (TGFβ1/2). Aer activation, the TGFβ receptor (comprised of two transmembrane serine/ threonine kinases - TβRI and TβRII) phosphorylates and activates Smad2 and Smad3 proteins which complex with co-Smad (Smad4), translocate to the nucleus and transcribe genes whose products regulate scarring (reviewed by (Finnson et al., 2013). Immediately aer injury, TGF-β1/2 levels rise rapidly, secreted fi rst by extravasated platelets and later by macrophages, leucocytes and reactive glia within damaged neural tissue (Border and Ruoslahti, 1992; Logan et al., 1992, 1999a; Logan et al.; Ahmed et al., 2014). TGF-β1/2 promote scarring by blocking the degradation of leptomeningeal fi broblast-derived ECM through suppression of the activity of metalloproteinases (MMP) and tissue plasminogen activator (tPA), released from endogenous glia (Border and Ruoslahti, 1992; Logan et al., 1992), and activation of tissue inhibitors of MMP (TIMP) and plasminogen activator inhibitor-1 (PAI-1) (Ahmed et al., 2014). Conversely, ECM deposition is increased in CNS wounds aer TGF-β1 administration (Logan et al., 1999a; Zhang et al., 2009) and in fl ammation and scarring are suppressed aer both treat-ment with TGF-β1/2 antibodies (Logan et al., 1999a) and the synthetic TβRI/II blockader LY-364947 (Yoshioka et al., 2011).

Other injury responsive growth factors include connective tissue growth factor (CTGF), hepatocyte growth factor and pro-inflammatory cytokinese.g., tumour necrosis factors (TNF) and interleukins (IL). CTGF promotes fibrobloblast cell adhesion and the production of the ECM components collagen I/III, the integrin β1 subunit and fibronectin in scars (Frazier et al., 1996; Vial et al., 2011), is expressed in reactive astrocytes, invading fibroblasts and endothelial cells in CNS wounds (Schwab et al., 2001) and regulated by TGF-β (Frazier et al., 1996). Hepatocyte growth factor (HGF) promotes the proliferation of macrophages by binding to its tyrosine kinase receptor cMet present on macrophages and NG2 producing synantocytes (Moransard et al., 2010). Pro-inflammatory cytokines bind to the toll-like family of receptors (TLR) expressed by microglia and astrocytes and effect their transformation into reactive phenotypes (Crack and Bray, 2007).

Decorin suppresses CNS scarring

Decorin is a small, leucine-rich, chondroitin-dermatan sulphate proteoglycan expressed by neurons and astrocytes in the CNS, but also sequestered in the ECM of many tissues (Hocking et al., 1998; Davies et al., 2004; Minor et al., 2008). Decorin is anti- fi brotic and anti-in fl ammatory in many tissues (Border and Ruoslahti, 1992; Hildebrand et al., 1994) including the brain (Logan et al., 1999) and greatly attenuates the formation of acute and causes the partial dissolution of established chronic SCI scars (Davies et al., 2004, 2006; Ahmed et al., 2014) by abrogating inflammation, CSPG/ ECM deposition, and glia and macrophage responses to injury (Lagord et al., 2002; Davies et al., 2004, 2006). More specifically, Decorin regulates scarring by: (1) blocking TβRI/II activation and subsequent signalling through Smad 2 and Smad 3 (Yamaguchi et al., 1990; Akhurst, 2006); (2) binding to type I collagen to inhibit fibrogenesis (Reese et al., 2013); (3) inhibiting CTGF activity (Vial et al., 2011); (4) inhibiting cell adhesion and fi broblast migration by binding to fi bronectin (Winnemoller et al., 1991); (5) stimulating the release of plasminogen from glia and its conversion to tPA (Davies et al., 2006); (6) regulation of angiogenesis (Neill et al., 2012) and in fl ammation (Hamada et al., 1996) by interaction with EGFR, cMet) and TLR; and (7) reducing mRNA and protein levels of Sema3A within CNS scar tissue (Minor et al., 2011; Ahmed et al., 2014) and suppressing Sema3A and fibronectin expression by invading leptomeningeal/ pericyte-derived fibroblasts (Minor et al., 2011). Decorin modulates the acute phase of scarring by suppression of injury-induced TGF-β1/2 (Logan et al., 1999a) and inhibition of cell adhesion and migration by sequestration of TGF-β1/2 after binding to fi bronectin (Zhang et al., 2009; Vial et al., 2011; Reese et al., 2013), and causes dissolution of the established chronic scar through induction of MMP and tPA activity and simultaneous suppression of TIMP and PAI-1 (Renckens et al., 2005; Davies et al., 2006; Ahmed et al., 2014). EGFR activation stimulates CSPG production (Asher et al., 2000; Dobbertin et al., 2003) and Decorin counteracts this activity by competing with EGF for EGFR binding (Yamaguchi et al., 1990; Logan et al., 1999a; Santra et al., 2000; Davies et al., 2004; Ahmed et al., 2014). Here, we review the use of Decorin both for suppression of acute CNS scar formation and for dissolution of the mature scar after SCI, and discuss the corollary that concomitant reductions in axon growth inhibitory ligands are conducive to the regeneration of spinal axons.

Decorin suppresses titres of axon growth inhibitors in SCI sites

The anti-scarring effects of Decorin signi fi cantly lower the build-up of titres of scar-derived axon growth inhibitors by degradation and suppression of their synthesis (Davies et al., 2004; Davies et al., 2006) in and around the SCI injury site, leading to reduced binding of inhibitory ligands to their receptors expressed on axon growth cones, including the protein tyrosine phosphatase receptor sigma (PTPRS) and the leucocyte common antigen related receptor (LAR) for CSPG (Shen et al., 2009; Sharma et al., 2012); the neuropilin/plexin receptor complex (reviewed by Sandvig et al., 2004) for Sema3A; and NgR and PirB for the myelin-derived inhibitory ligands (Liu et al., 2002; Wang et al., 2002). After ligand binding, these receptors activate intracellular signalling pathways which converge on the ras homolog gene family member A (RhoA)/Rho associated protein kinase (ROCK) (RhO/ ROCK) intracellular signalling pathway (which regulates actin polymerisation in axon growth cones) inducing growth arrest through growth cone collapse (Sandvig et al., 2004; Ahmed et al., 2014). However, it is not known if suppression of EGFR activity by Decorin (Iozzo et al., 1999; Csordas et al., 2000; Zhu et al., 2005) is correlated with concomitant inhibition of Rho/ROCK signalling to protect against growth cone collapse (Minor et al., 2011).

Axon regeneration in SCI lesions after Decorin treatment

The expectation that suppression of growth inhibitory ligands by Decorin would promote axon regeneration after SCI has not been realised since very few axons traverse Decorin-treated spinal cord wounds (Moon and Fawcett, 2001; Davies et al., 2004, 2006; Ahmed et al., 2014) and might be deemed counter-intuitive if the motoring analogy applies that releasing the brake will not initiate forward motion unless the accelerator is engaged. This concept implies that robust CNS axon regeneration may only be possible when disinhibitory (including anti-fibrotic) and axogenic treatments are combined and is borne out by the observations that treatment with an NgR signalling blocker must be supplemented with NTF to achieve axon growth through a CNS wound (Douglas et al., 2009; Berry et al., 2011). Nonetheless, Decorin does have limited axogenic properties, exemplifiedin vivoand by the growth of neurites in Decorin-treated adult dorsal root ganglion neurons grownon inhibitory CSPG and CNS myelin substrates without the presence of plasmin (Minor et al., 2008). Since EGFR blockade promotes some spinal cord motor neuron (Erschbamer et al., 2007) and retinal ganglion cell axon growth (Koprivica et al., 2005) (although the latter claim has been challenged by Douglas et al. (2009)), this axogenic e ff ect of Decorin has been attributed to the suppression of EGFR (Minor et al., 2008). NTF stimulate axon regeneration by activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which promotes axogenic protein synthesis and protects against growth cone collapse through down-stream mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β), respectively (Morgan-Warren et al., 2013). Moreover, NTF induce regulated intramembranous proteolysis (RIP) of the transmembrane p75/TROY signalling moieties of the NgR trimeric complex (Ahmed et al., 2005, 2006) blocking Rho/ROCK pathway-mediated depolymerisation of actin in growth cones thereby preserving their functional integrity. Moreover, it has been suggested that binding of Decorin to the transcription factor STAT3 regulates Sema3A expression and that activation of the ErB4 receptor (an EGFR family member) by Decorin suppresses STAT3 through suppressor of cytokine signalling 3 (SOCS3) and Src homology phosphatase-1 (SHP-1) production (Minor et al., 2011) resulting in reduced levels of Sema3A in a SCI wound.

The assertion that Decorin treatment is a panacea for SCI is tempered by the caveat that scar tissue may develop by default if axon regeneration fails, since scarring is universally absent in experimental CNS lesions when they are traversed by significant numbers of regenerating axons (Berry et al., 2008; Park et al., 2008; Liu et al., 2010); a phenomenon that may be explained by the observation that regenerating axons stimulate MMP/tPA release from astrocytes and inhibit the production of TIMP/PAI-1, thereby impairing the formation and promoting the dissolution of CNS scar tissue (Ahmed et al., 2005). Massive scarring and cavitation are unfailing sequelae of spinal cord trauma (Edgar and Quail, 1994; Fitch et al., 1999; Ahmed et al., 2014; Surey et al., 2014), demonstrating that the growth cones of the few axons spontaneously regenerate after SCI has no impact on scar deposition. Accordingly, we suggest that a combined NTF and Decorin treatment regimen would act synergistically to depress scar formation and have added value in promoting the regrowth of lost connections, offering the hope of functional recovery in SCI patients.

Conclusions

Delivery of Decorin to SCI sites greatly reduces scarring and the accumulation of associated axon growth inhibitory ligands in both acute and chronic scenarios, but has restricted effects on the promotion of axon growth. Thus, we suggest that return of function in SCI patients requires the application of a combined Decorin and NTF treatment.

Author statements:The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or theDepartment of Health.

Author contributions:Esmaeili M collated the literature and wrote the first manuscript draft. Berry M and Logan A contributed to manuscript writing. Ahmed Z was responsible for review conception and manuscript writing. All authors approved the final version of this paper.

Ahmed Z, Dent RG, Leadbeater WE, Smith C, Berry M, Logan A (2005) Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Mol Cell Neurosci 28:64-78.

Ahmed Z, Suggate EL, Brown ER, Dent RG, Armstrong SJ, Barrett LB, Berry M, Logan A (2006) Schwann cell-derived factor-induced modulation of the NgR/p75(NTR)/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. Brain 129:1517-1533.

Ahmed Z, Bansal D, Tizzard K, Surey S, Esmaeili M, Gonzalez AM, Berry M, Logan A (2014) Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds. Neurobiol Dis 64:163-176.

Akhurst RJ (2006) A sweet link between TGFbeta and vascular disease? Nat Genet 38:400-401.

Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, Levine JM, Margolis RU, Rogers JH, Fawcett JW (2000) Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J Neurosci 20:2427-2438.

Berry M, Ahmed Z, Lorber B, Douglas M, Logan A (2008) Regeneration of axons in the visual system. Restor Neurol Neurosci 26:147-174.

Berry M, Ahmed Z, Douglas MR, Logan A (2011) Epidermal growth factor receptor antagonists and CNS axon regeneration: mechanisms and controversies. Brain Res Bull 84:289-299.

Border WA, Ruoslahti E (1992) Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 90:1-7.

Bundesen LQ, Scheel TA, Bregman BS, Kromer LF (2003) Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J Neurosci 23:7789-7800.

Crack PJ, Bray PJ (2007) Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol 85:476-480.

Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197-207.

Csordas G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D, Nugent MA, Hajnoczky G, Iozzo RV (2000) Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo. J Biol Chem 275:32879-32887.

Davies JE, Tang X, Denning JW, Archibald SJ, Davies SJ (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.

Davies JE, Tang X, Bournat JC, Davies SJ (2006) Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro. J Neurotrauma 23:397-408.

Dobbertin A, Rhodes KE, Garwood J, Properzi F, Heck N, Rogers JH, Fawcett JW, Faissner A (2003) Regulation of RPTPbeta/phosphacan expression and glycosaminoglycan epitopes in injured brain and cytokine-treated glia. Mol Cell Neurosci 24:951-971.

Douglas MR, Morrison KC, Jacques SJ, Leadbeater WE, Gonzalez AM, Berry M, Logan A, Ahmed Z (2009) Off-target effects of epidermal growth factor receptor antagonists mediate retinal ganglion cell disinhibited axon growth. Brain 132:3102-3121.

Edgar R, Quail P (1994) Progressive post-traumatic cystic and non-cystic myelopathy. Br J Neurosurg 8:7-22.

Erschbamer M, Pernold K, Olson L (2007) Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. J Neurosci 27:6428-6435.

Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377-391.

Finnson KW, McLean S, Di Guglielmo GM, Philip A (2013) Dynamics of transforming growth factor beta signaling in wound healing and scarring. Adv Wound Care (New Rochelle) 2:195-214.

Fitch MT, Silver J (1997) Activated macrophages and the blood-brain barrier: in fl ammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 148:587-603.

Fitch MT, Doller C, Combs CK, Landreth GE, Silver J (1999) Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of in fl ammation-induced secondary injury after CNS trauma. J Neurosci 19:8182-8198.

Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR (1996) Stimulation of fi broblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 107:404-411.

Hamada Y, Ikata T, Katoh S, Katoh K, Niwa M, Tsutsumishita Y, Fukuzawa K (1996) Effects of exogenous transforming growth factor-beta 1 on spinal cord injury in rats. Neurosci Lett 203:97-100.

Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, Ruoslahti E (1994) Interaction of the small interstitial proteoglycans biglycan, decorin and fi bromodulin with transforming growth factor beta. Biochem J 302 ( Pt 2):527-534.

Hocking AM, Shinomura T, McQuillan DJ (1998) Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol 17:1-19.

Iozzo RV, Moscatello DK, McQuillan DJ, Eichstetter I (1999) Decorin is a biological ligand for the epidermal growth factor receptor. J Biol Chem 274:4489-4492.

Koprivica V, Cho KS, Park JB, Yiu G, Atwal J, Gore B, Kim JA, Lin E, Tessier-Lavigne M, Chen DF, He Z (2005) EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310:106-110.

Kundi S, Bicknell R, Ahmed Z (2013) The role of angiogenic and wound-healing factors after spinal cord injury in mammals. Neurosci Res 76:1-9.

Lagord C, Berry M, Logan A (2002) Expression of TGFbeta2 but not TGFbeta1 correlates with the deposition of scar tissue in the lesioned spinal cord. Mol Cell Neurosci 20:69-92.

Liu BP, Fournier A, GrandPre T, Strittmatter SM (2002) Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297:1190-1193.

Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z (2010) PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13:1075-1081.

Logan A, Baird A, Berry M (1999a) Decorin attenuates gliotic scar formation in the rat cerebral hemisphere. Exp Neurol 159:504-510.

Logan A, Frautschy SA, Gonzalez AM, Sporn MB, Baird A (1992) Enhanced expression of transforming growth factor beta 1 in the rat brain after a localized cerebral injury. Brain Res 587:216-225.

Logan A, Green J, Hunter A, Jackson R, Berry M (1999b) Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to transforming growth factor-beta2. Eur J Neurosci 11:2367-2374.

Mei F, Christin Chong SY, Chan JR (2013) Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration. Neurosci Bull 29:177-188.

Minor K, Tang X, Kahrilas G, Archibald SJ, Davies JE, Davies SJ (2008) Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiol Dis 32:88-95.

Minor KH, Bournat JC, Toscano N, Giger RJ, Davies SJ (2011) Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue. Brain 134:1140-1155.

Moon LD, Fawcett JW (2001) Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFbeta1 and beta2. Eur J Neurosci 14:1667-1677.

Moransard M, Sawitzky M, Fontana A, Suter T (2010) Expression of the HGF receptor c-met by macrophages in experimental autoimmune encephalomyelitis. Glia 58:559-571.

Morgan-Warren PJ, Berry M, Ahmed Z, Scott RA, Logan A (2013) Exploiting mTOR signaling: a novel translatable treatment strategy for traumatic optic neuropathy? Invest Ophth Vis Sci 54:6903-6916.

Neill T, Schaefer L, Iozzo RV (2012) Decorin: a guardian from the matrix. Am J Pathol 181:380-387.

Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu BG, Connolly L, Kramvis I, Sahin M, He ZG (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322:963-966.

Reese SP, Underwood CJ, Weiss JA (2013) Effects of decorin proteoglycan on fi brillogenesis, ultrastructure, and mechanics of type I collagen gels. Matrix Biol 32:414-423.

Renckens R, Roelofs JJ, de Waard V, Florquin S, Lijnen HR, Carmeliet P, van der Poll T (2005) The role of plasminogen activator inhibitor type 1 in the in fl ammatory response to local tissue injury. J Thromb Haemost 3:1018-1025.

Sandvig A, Berry M, Barrett LB, Butt A, Logan A (2004) Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. Glia 46:225-251.

Santra M, Eichstetter I, Iozzo RV (2000) An anti-oncogenic role for decorin. Down-regulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells. J Biol Chem 275:35153-35161.

Schwab JM, Beschorner R, Nguyen TD, Meyermann R, Schluesener HJ (2001) Differential cellular accumulation of connective tissue growth factor de fi nes a subset of reactive astrocytes, invading fi broblasts, and endothelial cells following central nervous system injury in rats and humans. J Neurotrauma 18:377-388.

Sharma K, Selzer ME, Li S (2012) Scar-mediated inhibition and CSPG receptors in the CNS. Exp Neurol 237:370-378.

Shen Y, Tenney AP, Busch SA, Horn KP, Cuascut FX, Liu K, He Z, Silver J, Flanagan JG (2009) PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326:592-596.

Surey S, Berry M, Logan A, Bicknell R, Ahmed Z (2014) Differential cavitation, angiogenesis and wound-healing responses in injured mouse and rat spinal cords. Neuroscience 275C:62-80.

Vial C, Gutierrez J, Santander C, Cabrera D, Brandan E (2011) Decorin interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity. J Biol Chem 286:24242-24252.

Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941-944.

Winnemoller M, Schmidt G, Kresse H (1991) In fl uence of decorin on fi broblast adhesion to fi bronectin. Eur J Cell Biol 54:10-17.

Yamaguchi Y, Mann DM, Ruoslahti E (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346:281-284.

Yoshioka N, Kimura-Kuroda J, Saito T, Kawamura K, Hisanaga S, Kawano H (2011) Small molecule inhibitor of type I transforming growth factor-beta receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons. J Neurosci Res 89:381-393.

Zhang G, Chen S, Goldoni S, Calder BW, Simpson HC, Owens RT, Mc-Quillan DJ, Young MF, Iozzo RV, Birk DE (2009) Genetic evidence for the coordinated regulation of collagen fi brillogenesis in the cornea by decorin and biglycan. J Biol Chem 284:8888-8897.

Zhu JX, Goldoni S, Bix G, Owens RT, McQuillan DJ, Reed CC, Iozzo RV (2005) Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis. J Biol Chem 280:32468-32479.

Zubair Ahmed, Ph.D., Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Room WX2.17 Institute of Biomedical Research (West), Edgbaston, Birmingham B15 2TT, UK, z.ahmed.1@bham.ac.uk.

10.4103/1673-5374.141797

http://www.nrronline.org/

Accepted: 2014-08-18