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The role of TGF-β in the pathogenesis of primary open-angle glaucoma

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Abstract

Transforming growth factor-β2 (TGF-β2) is found in increasing amounts in aqueous humor and reactive optic nerve astrocytes of patients with primary open-angle glaucoma (POAG), a major cause of blindness worldwide. The available data strongly indicate that TGF-β2 is a key player contributing to the structural changes in the extracellular matrix (ECM) of the trabecular meshwork and optic nerve head as characteristically seen in POAG. The changes involve an induction in the expression of various ECM molecules and are remarkably similar in trabecular meshwork cells and optic nerve head astrocytes. The ECM changes in the trabecular meshwork most probably play a role in the increase of aqueous humor outflow resistance causing higher intraocular pressure (IOP). In the optic nerve head, TGF-β2-induced changes might contribute to deformation of the optic nerve axons causing impairment of axonal transport and neurotrophic supply and leading to their continuous degeneration. The increase in IOP further adds mechanical stress and strain to optic nerve axons and accelerates degenerative changes. In addition, high IOP might induce the expression of activated TGF-β1 in trabecular meshwork cells and optic nerve head astrocytes; this again might significantly lead to the progress of axonal degeneration. The action of TGF-β2 in POAG is largely mediated through the connective tissue growth factor, whereas the activities of TGF-β1 and -β2 are modulated by the blocking effects of bone morphogenetic protein-4 (BMP-4) and BMP-7, by gremlin that inhibits BMP signaling and by several species of microRNAs.

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References

  • Adams JC (2001) Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol 17:25–51

    PubMed  CAS  Google Scholar 

  • Allen JB, Davidson MG, Nasisse MP, Fleisher LN, McGahan MC (1998) The lens influences aqueous humor levels of transforming growth factor-beta 2. Graefes Arch Clin Exp Ophthalmol 236:305–311

    PubMed  CAS  Google Scholar 

  • Alm A, Nilsson SF (2009) Uveoscleral outflow—a review. Exp Eye Res 88:760–768

    PubMed  CAS  Google Scholar 

  • Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFβ activation. J Cell Sci 116:217–224

    PubMed  CAS  Google Scholar 

  • Attisano L, Wrana JL (2002) Signal transduction by the TGF-beta superfamily. Science 296:1646–1647

    PubMed  CAS  Google Scholar 

  • Bachmann B, Birke M, Kook D, Eichhorn M, Lütjen-Drecoll E (2006) Ultrastructural and biochemical evaluation of the porcine anterior chamber perfusion model. Invest Ophthalmol Vis Sci 47:2011–2020

    PubMed  Google Scholar 

  • Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    PubMed  CAS  Google Scholar 

  • Bhattacharya SK, Rockwood EJ, Smith SD, Bonilha VL, Crabb JS, Kuchtey RW, Robertson NG, Peachey NS, Morton CC, Crabb JW (2005) Proteomics reveal cochlin deposits associated with glaucomatous trabecular meshwork. J Biol Chem 280:6080–6084

    PubMed  CAS  Google Scholar 

  • Bhattacharya SK, Gabelt BT, Ruiz J, Picciani R, Kaufman PL (2009) Cochlin expression in anterior segment organ culture models after TGFbeta2 treatment. Invest Ophthalmol Vis Sci 50:551–559

    PubMed  Google Scholar 

  • Bollinger KE, Crabb JS, Yuan X, Putliwala T, Clark AF, Crabb JW (2011) Quantitative proteomics: TGF{beta}2-signaling in trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:8287–8294

    PubMed  Google Scholar 

  • Bornstein P (2001) Thrombospondins as matricellular modulators of cell function. J Clin Invest 107:929–934

    PubMed  CAS  Google Scholar 

  • Bradley JM, Vranka J, Colvis CM, Conger DM, Alexander JP, Fisk AS, Samples JR, Acott TS (1998) Effect of matrix metalloproteinases activity on outflow in perfused human organ culture. Invest Ophthalmol Vis Sci 39:2649–2658

    PubMed  CAS  Google Scholar 

  • Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A (2011) Bone morphogenetic proteins: a critical review. Cell Signal 23:609–620

    PubMed  CAS  Google Scholar 

  • Brubaker RF (1991) Flow of aqueous humor in humans (the Friedenwald Lecture). Invest Ophthalmol Vis Sci 32:3145–3166

    PubMed  CAS  Google Scholar 

  • Burgoyne CF (2011) A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res 93:120–132

    PubMed  Google Scholar 

  • Chand HS, Foster DC, Kisiel W (2005) Structure, function and biology of tissue factor pathway inhibitor-2. Thromb Haemost 94:1122–1130

    PubMed  CAS  Google Scholar 

  • Chen D, Zhao M, Mundy GR (2004) Bone morphogenetic proteins. Growth Factors 22:233–241

    PubMed  CAS  Google Scholar 

  • Chen J, Li H, SundarRaj N, Wang JH (2007) Alpha-smooth muscle actin expression enhances cell traction force. Cell Motil Cytoskeleton 64:248–257

    PubMed  CAS  Google Scholar 

  • Clark AF, Wordinger RJ (2009) The role of steroids in outflow resistance. Exp Eye Res 88:752–759

    PubMed  CAS  Google Scholar 

  • Clark AF, Wilson K, McCartney MD, Miggans ST, Kunkle M, Howe W (1994) Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci 35:281–294

    PubMed  CAS  Google Scholar 

  • Clark AF, Miggans ST, Wilson K, Browder S, McCartney MD (1995) Cytoskeletal changes in cultured human glaucoma trabecular meshwork cells. J Glaucoma 4:183–188

    PubMed  CAS  Google Scholar 

  • Clark AF, Brotchie D, Read AT, Hellberg P, English-Wright S, Pang IH, Ethier CR, Grierson I (2005) Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue. Cell Motil Cytoskeleton 60:83–95

    PubMed  CAS  Google Scholar 

  • Collaborative Normal-Tension Glaucoma Study Group (1998a) Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 126:487–497

    Google Scholar 

  • Collaborative Normal-Tension Glaucoma Study Group (1998b) The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 126:498–505

    Google Scholar 

  • Cousins SW, McCabe MM, Danielpour D, Streilein JW (1991) Identification of transforming growth factor-beta as an immunosuppresive factor in aqueous humor. Invest Ophthalmol Vis Sci 32:2201–2211

    PubMed  CAS  Google Scholar 

  • Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N (1998) Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93:1159–1170

    PubMed  CAS  Google Scholar 

  • Dan J, Belyea D, Gertner G, Leshem I, Lusky M, Miskin R (2005) Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma. Arch Ophthalmol 123:220–224

    PubMed  CAS  Google Scholar 

  • Derhaschnig U, Shehata M, Herkner H, Bur A, Woisetschlager C, Laggner AN, Hirschl MM (2002) Increased levels of transforming growth factor-beta1 in essential hypertension. Am J Hypertens 15:207–211

    PubMed  CAS  Google Scholar 

  • Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111

    PubMed  CAS  Google Scholar 

  • Dijke P ten, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29:265–273

    PubMed  Google Scholar 

  • Filla MS, Woods A, Kaufman PL, Peters DM (2006) Beta1 and beta3 integrins cooperate to induce syndecan-4-containing cross-linked actin networks in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 47:1956–1967

    PubMed  Google Scholar 

  • Filla MS, Schwinn MK, Nosie AK, Clark RW, Peters DM (2011) Dexamethasone-associated cross-linked actin network formation in human trabecular meshwork cells involves beta3 integrin signaling. Invest Ophthalmol Vis Sci 52:2952–2959

    PubMed  CAS  Google Scholar 

  • Fleenor DL, Shepard AR, Hellberg PE, Jacobson N, Pang IH, Clark AF (2006) TGFbeta2-induced changes in human trabecular meshwork: implications for intraocular pressure. Invest Ophthalmol Vis Sci 47:226–234

    PubMed  Google Scholar 

  • Flügel C, Tamm E, Lütjen-Drecoll E, Stefani FH (1992) Age-related loss of α-smooth muscle actin in normal and glaucomatous human trabecular meshwork of different age groups. J Glaucoma 1:165–173

    Google Scholar 

  • Flügel-Koch C, Ohlmann A, Piatigorsky J, Tamm ER (2002) Disruption of anterior segment development by TGF-beta1 overexpression in the eyes of transgenic mice. Dev Dyn 225:111–125

    PubMed  Google Scholar 

  • Flügel-Koch C, Ohlmann A, Fuchshofer R, Welge-Lüssen U, Tamm ER (2004) Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-beta1 and dexamethasone in vitro. Exp Eye Res 79:649–663

    PubMed  Google Scholar 

  • Foster PJ, Buhrmann R, Quigley HA, Johnson GJ (2002) The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86:238–242

    PubMed  Google Scholar 

  • Fuchshofer R, Tamm ER (2009) Modulation of extracellular matrix turnover in the trabecular meshwork. Exp Eye Res 88:683–688

    PubMed  CAS  Google Scholar 

  • Fuchshofer R, Welge-Lüssen U, Lütjen-Drecoll E (2003) The effect of TGF-beta2 on human trabecular meshwork extracellular proteolytic system. Exp Eye Res 77:757–765

    PubMed  CAS  Google Scholar 

  • Fuchshofer R, Birke M, Welge-Lüssen U, Kook D, Lütjen-Drecoll E (2005) Transforming growth factor-beta 2 modulated extracellular matrix component expression in cultured human optic nerve head astrocytes. Invest Ophthalmol Vis Sci 46:568–578

    PubMed  Google Scholar 

  • Fuchshofer R, Yu AH, Welge-Lüssen U, Tamm ER (2007) Bone morphogenetic protein-7 is an antagonist of transforming growth factor-beta2 in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 48:715–726

    PubMed  Google Scholar 

  • Fuchshofer R, Stephan DA, Russell P, Tamm ER (2009) Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: identification of Smad7 as a critical inhibitor of TGF-beta2 signaling. Exp Eye Res 88:1020–1032

    PubMed  CAS  Google Scholar 

  • Gamulescu MA, Chen Y, He S, Spee C, Jin M, Ryan SJ, Hinton DR (2006) Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells: regulation by extracellular matrix proteins and hepatocyte growth factor. Exp Eye Res 83:212–222

    PubMed  CAS  Google Scholar 

  • Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Kass MA (2002) The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120:714–720

    PubMed  Google Scholar 

  • Gordon WE 3rd, Bushnell A (1979) Immunofluorescent and ultrastructural studies of polygonal microfilament networks in respreading non-muscle cells. Exp Cell Res 120:335–348

    PubMed  CAS  Google Scholar 

  • Gordon-Thomson C, Iongh RU de, Hales AM, Chamberlain CG, McAvoy JW (1998) Differential cataractogenic potency of TGF-beta1, -beta2, and -beta3 and their expression in the postnatal rat eye. Invest Ophthalmol Vis Sci 39:1399–1409

    PubMed  CAS  Google Scholar 

  • Gottanka J, Chan D, Eichhorn M, Lütjen-Drecoll E, Ethier CR (2004) Effects of TGF-β2 in perfused human eyes. Invest Ophthalmol Vis Sci 45:153–158

    PubMed  Google Scholar 

  • Gottanka J, Kuhlmann A, Scholz M, Johnson DH, Lutjen-Drecoll E (2005) Pathophysiologic changes in the optic nerves of eyes with primary open angle and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci 46:4170–4181

    PubMed  Google Scholar 

  • Granstein RD, Staszewski R, Knisley TL, Zeira E, Nazareno R, Latina M, Albert DM (1990) Aqueous humor contains transforming growth factor-β and a small (<3500 Daltons) inhibitor of thymocyte proliferation. J Immunol 144:3021–3027

    PubMed  CAS  Google Scholar 

  • Grant WM (1951) Clinical measurements of aqueous outflow. AMA Arch Ophthalmol 46:113–131

    PubMed  CAS  Google Scholar 

  • Grant WM (1963) Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 69:783–801

    PubMed  CAS  Google Scholar 

  • Gressner AM, Weiskirchen R (2006) Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 10:76–99

    PubMed  CAS  Google Scholar 

  • Hales AM, Chamberlain CG, McAvoy JW (2000) Susceptibility to TGFbeta2-induced cataract increases with aging in the rat. Invest Ophthalmol Vis Sci 41:3544–3551

    PubMed  CAS  Google Scholar 

  • Han H, Wecker T, Grehn F, Schlunck G (2011) Elasticity-dependent modulation of TGF-beta responses in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:2889–2896

    PubMed  CAS  Google Scholar 

  • Helbig H, Kittredge KL, Coca-Prados M, Davis J, Palestine AG, Nussenblatt RB (1991) Mammalian ciliary-body epithelial cells in culture produce transforming growth factor-beta. Graefes Arch Clin Exp Ophthalmol 229:84–87

    PubMed  CAS  Google Scholar 

  • Hernandez MR (2000) The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res 19:297–321

    PubMed  CAS  Google Scholar 

  • Hernandez MR, Pena JD (1997) The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol 115:389–395

    PubMed  CAS  Google Scholar 

  • Hernandez MR, Igoe F, Neufeld AH (1988) Cell culture of the human lamina cribrosa. Invest Ophthalmol Vis Sci 29:78–89

    PubMed  CAS  Google Scholar 

  • Hernandez MR, Andrzejewska WM, Neufeld AH (1990) Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. Am J Ophthalmol 109:180–188

    PubMed  CAS  Google Scholar 

  • Hernandez MR, Ye H, Roy S (1994) Collagen type IV gene expression in human optic nerve heads with primary open angle glaucoma. Exp Eye Res 59:41–51

    PubMed  CAS  Google Scholar 

  • Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C (2001) Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell 12:2730–2741

    PubMed  CAS  Google Scholar 

  • Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170:1807–1816

    PubMed  CAS  Google Scholar 

  • Hoare MJ, Grierson I, Brotchie D, Pollock N, Cracknell K, Clark AF (2009) Cross-linked actin networks (CLANs) in the trabecular meshwork of the normal and glaucomatous human eye in situ. Invest Ophthalmol Vis Sci 50:1255–1263

    PubMed  Google Scholar 

  • Huggins JT, Sahn SA (2004) Causes and management of pleural fibrosis. Respirology 9:441–447

    PubMed  Google Scholar 

  • Ihn H (2002a) The role of TGF-beta signaling in the pathogenesis of fibrosis in scleroderma. Arch Immunol Ther Exp (Warsz) 50:325–331

    CAS  Google Scholar 

  • Ihn H (2002b) Pathogenesis of fibrosis: role of TGF-β and CTGF. Curr Opin Rheumatol 14:681–685

    PubMed  CAS  Google Scholar 

  • Inatani M, Tanihara H, Katsuta H, Honjo M, Kido N, Honda Y (2001) Transforming growth factor-β2 levels in aqueous humor of glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol 239:109–113

    PubMed  CAS  Google Scholar 

  • Itoh S, Dijke P ten (2007) Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol 19:176–184

    PubMed  CAS  Google Scholar 

  • Jampel HD, Roche N, Stark WJ, Roberts AB (1990) Transforming growth factor-β in human aqueous humor. Curr Eye Res 9:963–969

    PubMed  CAS  Google Scholar 

  • Jester JV, Barry-Lane PA, Cavanagh HD, Petroll WM (1996) Induction of alpha-smooth muscle actin expression and myofibroblast transformation in cultured corneal keratocytes. Cornea 15:505–516

    PubMed  CAS  Google Scholar 

  • Johnson DH, Tschumper RC (1989) The effect of organ culture on human trabecular meshwork. Exp Eye Res 49:113–127

    PubMed  CAS  Google Scholar 

  • Johnson M (2006) What controls aqueous humour outflow resistance? Exp Eye Res 82:545–557

    PubMed  CAS  Google Scholar 

  • Johnson M, Erickson K (2000) Mechanisms and routes of aqueous humor drainage. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology. Saunders, Philadelphia, pp 2577–2595

    Google Scholar 

  • Johnson M, Chan D, Read AT, Christensen C, Sit A, Ethier CR (2002) The pore density in the inner wall endothelium of Schlemm's canal of glaucomatous eyes. Invest Ophthalmol Vis Sci 43:2950–2955

    PubMed  Google Scholar 

  • Junglas B, Yu AH, Welge-Lussen U, Tamm ER, Fuchshofer R (2009) Connective tissue growth factor induces extracellular matrix deposition in human trabecular meshwork cells. Exp Eye Res 88:1065–1075

    PubMed  CAS  Google Scholar 

  • Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO (2002) The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 120:701–713

    PubMed  Google Scholar 

  • Kater AW de, Shahsafaei A, Epstein DL (1992) Localization of smooth muscle and nonmuscle actin isoforms in the human aqueous outflow pathway. Invest Ophthalmol Vis Sci 33:424–429

    PubMed  Google Scholar 

  • Kirwan RP, Crean JK, Fenerty CH, Clark AF, O'Brien CJ (2004) Effect of cyclical mechanical stretch and exogenous transforming growth factor-beta1 on matrix metalloproteinase-2 activity in lamina cribrosa cells from the human optic nerve head. J Glaucoma 13:327–334

    PubMed  Google Scholar 

  • Kirwan RP, Leonard MO, Murphy M, Clark AF, O'Brien CJ (2005) Transforming growth factor-beta-regulated gene transcription and protein expression in human GFAP-negative lamina cribrosa cells. Glia 52:309–324

    PubMed  Google Scholar 

  • Kirwan RP, Wordinger RJ, Clark AF, O'Brien CJ (2009) Differential global and extra-cellular matrix focused gene expression patterns between normal and glaucomatous human lamina cribrosa cells. Mol Vis 15:76–88

    PubMed  CAS  Google Scholar 

  • Küchle M, Vinores SA, Mahlow J, Green WR (1996) Blood-aqueous barrier in pseudoexfoliation syndrome: evaluation by immunohistochemical staining of endogenous albumin. Graefes Arch Clin Exp Ophthalmol 234:12–18

    PubMed  Google Scholar 

  • Kusakabe M, Cheong PL, Nikfar R, McLennan IS, Koishi K (2008) The structure of the TGF-beta latency associated peptide region determines the ability of the proprotein convertase furin to cleave TGF-betas. J Cell Biochem 103:311–320

    PubMed  CAS  Google Scholar 

  • Kwon YH, Fingert JH, Kuehn MH, Alward WL (2009) Primary open-angle glaucoma. N Engl J Med 360:1113–1124

    PubMed  CAS  Google Scholar 

  • Lamouille S, Derynck R (2010) Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs 193:8–22

    PubMed  Google Scholar 

  • Last JA, Pan T, Ding Y, Reilly CM, Keller K, Acott TS, Fautsch MP, Murphy CJ, Russell P (2011) Elastic modulus determination of normal and glaucomatous human trabecular meshwork. Invest Ophthalmol Vis Sci 52:2147–2152

    PubMed  Google Scholar 

  • Lazarides E (1976) Actin, alpha-actinin, and tropomyosin interaction in the structural organization of actin filaments in nonmuscle cells. J Cell Biol 68:202–219

    PubMed  CAS  Google Scholar 

  • Lepple-Wienhues A, Stahl F, Wiederholt M (1991) Differential smooth muscle-like contractile properties of trabecular meshwork and ciliary muscle. Exp Eye Res 53:33–38

    PubMed  CAS  Google Scholar 

  • Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E (2003) Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 121:48–56

    PubMed  Google Scholar 

  • Li J, Tripathi BJ, Tripathi RC (2000) Modulation of pre-mRNA splicing and protein production of fibronectin by TGF-β2 in porcine trabecular cells. Invest Ophthalmol Vis Sci 41:3437–3443

    PubMed  CAS  Google Scholar 

  • Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, Mills RP (2001) Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 108:1943–1953

    PubMed  CAS  Google Scholar 

  • Liton PB, Liu X, Challa P, Epstein DL, Gonzalez P (2005) Induction of TGF-beta1 in the trabecular meshwork under cyclic mechanical stress. J Cell Physiol 205:364–371

    PubMed  CAS  Google Scholar 

  • Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217

    PubMed  CAS  Google Scholar 

  • Luna C, Li G, Qiu J, Epstein DL, Gonzalez P (2011a) MicroRNA-24 regulates the processing of latent TGFbeta1 during cyclic mechanical stress in human trabecular meshwork cells through direct targeting of FURIN. J Cell Physiol 226:1407–1414

    PubMed  CAS  Google Scholar 

  • Luna C, Li G, Qiu J, Epstein DL, Gonzalez P (2011b) Cross-talk between miR-29 and transforming growth factor-betas in trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:3567–3572

    PubMed  CAS  Google Scholar 

  • Lütjen-Drecoll E (2005) Morphological changes in glaucomatous eyes and the role of TGFbeta2 for the pathogenesis of the disease. Exp Eye Res 81:1–4

    PubMed  Google Scholar 

  • Lütjen-Drecoll E, Shimizu T, Rohrbach M, Rohen JW (1986) Quantitative analysis of "plaque material" in the inner and outer wall of Schlemm's canal in normal and glaucomatous eyes. Exp Eye Res 42:443–455

    PubMed  Google Scholar 

  • Margadant C, Sonnenberg A (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 11:97–105

    PubMed  CAS  Google Scholar 

  • Min SH, Lee TI, Chung YS, Kim HK (2006) Transforming growth factor-beta levels in human aqueous humor of glaucomatous, diabetic and uveitic eyes. Korean J Ophthalmol 20:162–165

    PubMed  Google Scholar 

  • Miyazono K, Kamiya Y, Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147:35–51

    PubMed  CAS  Google Scholar 

  • Murphy-Ullrich JE, Poczatek M (2000) Activation of latent TGF-β by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev 11:59–69

    PubMed  CAS  Google Scholar 

  • Nakamura Y, Hirano S, Suzuki K, Seki K, Sagara T, Nishida T (2002) Signaling mechanism of TGF-beta1-induced collagen contraction mediated by bovine trabecular meshwork cells. Invest Ophthalmol Vis Sci 43:3465–3472

    PubMed  Google Scholar 

  • Neufeld AH, Liu B (2003) Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist 9:485–495

    PubMed  CAS  Google Scholar 

  • Neufeld AH, Hernandez MR, Gonzalez M (1997) Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 115:497–503

    PubMed  CAS  Google Scholar 

  • Neumann C, Yu A, Welge-Lussen U, Lutjen-Drecoll E, Birke M (2008) The effect of TGF-beta2 on elastin, type VI collagen, and components of the proteolytic degradation system in human optic nerve astrocytes. Invest Ophthalmol Vis Sci 49:1464–1472

    PubMed  Google Scholar 

  • Nishimura SL (2009) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 175:1362–1370

    PubMed  CAS  Google Scholar 

  • Ochiai Y, Ochiai H (2002) Higher concentration of transforming growth factor-beta in aqueous humor of glaucomatous eyes and diabetic eyes. Jpn J Ophthalmol 46:249–253

    PubMed  CAS  Google Scholar 

  • Ohji M, Sundarraj N, Thoft RA (1993) Transforming growth factor-beta stimulates collagen and fibronectin synthesis by human corneal stromal fibroblasts in vitro. Curr Eye Res 12:703–709

    CAS  Google Scholar 

  • O'Reilly S, Pollock N, Currie L, Paraoan L, Clark AF, Grierson I (2011) Inducers of cross-linked actin networks (CLANs) in trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:7316–7324

    PubMed  Google Scholar 

  • Overby DR, Stamer WD, Johnson M (2009) The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium. Exp Eye Res 88:656–670

    PubMed  CAS  Google Scholar 

  • Ozcan AA, Ozdemir N, Canataroglu A (2004) The aqueous levels of TGF-beta2 in patients with glaucoma. Int Ophthalmol 25:19–22

    PubMed  Google Scholar 

  • Park SH (2005) Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 38:9–16

    PubMed  Google Scholar 

  • Pasquale LR, Dorman-Pease ME, Lutty GA, Quigley HA, Jampel HD (1993) Immunolocalization of TGF-β1, TGF-β2, and TGF-β3 in the anterior segment of the human eye. Invest Ophthalmol Vis Sci 34:23–30

    PubMed  CAS  Google Scholar 

  • Pattabiraman PP, Rao PV (2010) Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol 298:C749–C763

    PubMed  CAS  Google Scholar 

  • Pena JD, Roy S, Hernandez MR (1996) Tropoelastin gene expression in optic nerve heads of normal and glaucomatous subjects. Matrix Biol 15:323–330

    PubMed  CAS  Google Scholar 

  • Pena JD, Netland PA, Vidal I, Dorr DA, Rasky A, Hernandez MR (1998) Elastosis of the lamina cribrosa in glaucomatous optic neuropathy. Exp Eye Res 67:517–524

    PubMed  CAS  Google Scholar 

  • Pena JD, Taylor AW, Ricard CS, Vidal I, Hernandez MR (1999) Transforming growth factor beta isoforms in human optic nerve heads. Br J Ophthalmol 83:209–218

    PubMed  CAS  Google Scholar 

  • Pfeffer BA, Flanders KC, Guerin CJ, Danielpour D, Anderson DH (1994) Transforming growth factor beta 2 is the predominant isoform in the neural retina, retinal pigment epithelium-choroid and vitreous of the monkey eye. Exp Eye Res 59:323–333

    PubMed  CAS  Google Scholar 

  • Phanish MK, Winn SK, Dockrell ME (2009) Connective tissue growth factor-(CTGF, CCN2)–a marker, mediator and therapeutic target for renal fibrosis. Nephron Exp Nephrol 114:e83–e92

    PubMed  Google Scholar 

  • Picht G, Welge-Luessen U, Grehn F, Lütjen-Drecoll E (2001) Transforming growth factor-β2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development. Graefes Arch Clin Exp Ophthalmol 239:199–207

    PubMed  CAS  Google Scholar 

  • Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18:39–57

    PubMed  CAS  Google Scholar 

  • Quigley HA (2011) Glaucoma. Lancet 377:1367–1377

    PubMed  Google Scholar 

  • Quigley HA, Hohman RM, Addicks EM, Massof RW, Green WR (1983) Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 95:673–691

    PubMed  CAS  Google Scholar 

  • Read AT, Chan DW, Ethier CR (2006) Actin structure in the outflow tract of normal and glaucomatous eyes. Exp Eye Res 82:974–985

    PubMed  CAS  Google Scholar 

  • Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851

    PubMed  Google Scholar 

  • Ritch R, Schlötzer-Schrehardt U, Konstas AG (2003) Why is glaucoma associated with exfoliation syndrome? Prog Retin Eye Res 22:253–275

    PubMed  Google Scholar 

  • Robertson JV, Golesic E, Gauldie J, West-Mays JA (2010) Ocular gene transfer of active TGF-beta induces changes in anterior segment morphology and elevated IOP in rats. Invest Ophthalmol Vis Sci 51:308–318

    PubMed  Google Scholar 

  • Rohen JW, Witmer R (1972) Electron microscopic studies on the trabecular meshwork in glaucoma simplex. Albrecht v Graefes Arch Klin Exp Ophthalmol 183:251–266

    CAS  Google Scholar 

  • Ronnov-Jessen L, Petersen OW (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68:696–707

    PubMed  CAS  Google Scholar 

  • Saika S, Ikeda K, Yamanaka O, Flanders KC, Nakajima Y, Miyamoto T, Ohnishi Y, Kao WW, Muragaki Y, Ooshima A (2005) Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali injury model in mice. Lab Invest 85:474–486

    PubMed  CAS  Google Scholar 

  • Saika S, Ikeda K, Yamanaka O, Flanders KC, Ohnishi Y, Nakajima Y, Muragaki Y, Ooshima A (2006) Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am J Physiol Cell Physiol 290:C282–C289

    PubMed  CAS  Google Scholar 

  • Schlötzer-Schrehardt U, Zenkel M, Küchle M, Sakai LY, Naumann GO (2001) Role of transforming growth factor-beta1 and its latent form binding protein in pseudoexfoliation syndrome. Exp Eye Res 73:765–780

    PubMed  Google Scholar 

  • Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC (2003) TGF-β signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol 284:F243–F252

    PubMed  CAS  Google Scholar 

  • Sethi A, Jain A, Zode GS, Wordinger RJ, Clark AF (2011a) Role of TGFbeta/Smad signaling in gremlin induction of human trabecular meshwork extracellular matrix proteins. Invest Ophthalmol Vis Sci 52:5251–5259

    Google Scholar 

  • Sethi A, Mao W, Wordinger RJ, Clark AF (2011b) Transforming growth factor-beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) genes in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:5240–5250

    PubMed  CAS  Google Scholar 

  • Shepard AR, Millar JC, Pang IH, Jacobson N, Wang WH, Clark AF (2010) Adenoviral gene transfer of active human transforming growth factor-{beta}2 elevates intraocular pressure and reduces outflow facility in rodent eyes. Invest Ophthalmol Vis Sci 51:2067–2076

    PubMed  Google Scholar 

  • Shuman MA, Polansky JR, Merkel C, Alvarado JA (1988) Tissue plasminogen activator in cultured human trabecular meshwork cells. Predominance of enzyme over plasminogen activator inhibitor. Invest Ophthalmol Vis Sci 29:401–405

    PubMed  CAS  Google Scholar 

  • Sieber C, Kopf J, Hiepen C, Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev 20:343–355

    PubMed  CAS  Google Scholar 

  • Tamm ER (2009a) The role of the ciliary body in aqueous humor dynamics: structural aspects. In: Besharse J, Dana R, Dartt D (eds) Encyclopedia of the eye. Academic Press, Oxford, pp 179–186

    Google Scholar 

  • Tamm ER (2009b) The trabecular meshwork outflow pathways. Functional morphology and surgical aspects. In: Shaarawy TM, Sherwood MB, Hitchings RA, Crowston JG (eds) Glaucoma, vol II. Saunders, Elsevier, Amsterdam, pp 31–44

    Google Scholar 

  • Tamm ER (2009c) The trabecular meshwork outflow pathways: structural and functional aspects. Exp Eye Res 88:648–655

    PubMed  CAS  Google Scholar 

  • Tamm ER, Fuchshofer R (2007) What increases outflow resistance in primary open-angle glaucoma? Surv Ophthalmol 52 (Suppl 2):S101–S104

    PubMed  Google Scholar 

  • Tamm ER, Lütjen-Drecoll E (1996) Ciliary body. Microscop Res Tech 33:390–439

    CAS  Google Scholar 

  • Tamm E, Flügel C, Stefani FH, Rohen JW (1992) Contractile cells in the human scleral spur. Exp Eye Res 54:531–543

    PubMed  CAS  Google Scholar 

  • Tamm ER, Siegner A, Baur A, Lutjen-Drecoll E (1996) Transforming growth factor-beta 1 induces alpha-smooth muscle-actin expression in cultured human and monkey trabecular meshwork. Exp Eye Res 62:389–397

    PubMed  CAS  Google Scholar 

  • Tamm E, Russell P, Epstein DL, Johnson DH, Piatigorsky J (1999) Modulation of Myocilin/TIGR expression in human trabecular meshwork. Invest Ophthalmol Vis Sci 40:2577–2582

    PubMed  CAS  Google Scholar 

  • Tamm ER, Toris CB, Crowston JG, Sit A, Lim S, Lambrou G, Alm A (2007) Basic science of intraocular pressure. In: Weinreb RN, Brandt JD, Garway-Heath D, Medeiros F (eds) Intraocular pressure. Reports and consensus statements of the 4th global AIGS consensus meeting on intraocular pressure. Kugler, Amsterdam, pp 1–14

    Google Scholar 

  • Tektas OY, Lütjen-Drecoll E (2009) Structural changes of the trabecular meshwork in different kinds of glaucoma. Exp Eye Res 88:769–775

    PubMed  CAS  Google Scholar 

  • The AGIS Investigators (2000) The advanced glaucoma intervention study (AGIS). 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429–440

    Google Scholar 

  • Tian B, Geiger B, Epstein DL, Kaufman PL (2000) Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci 41:619–623

    PubMed  CAS  Google Scholar 

  • Tian B, Gabelt BT, Geiger B, Kaufman PL (2009) The role of the actomyosin system in regulating trabecular fluid outflow. Exp Eye Res 88:713–717

    PubMed  CAS  Google Scholar 

  • Tomarev SI, Wistow G, Raymond V, Dubois S, Malyukova I (2003) Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis. Invest Ophthalmol Vis Sci 44:2588–2596

    PubMed  Google Scholar 

  • Tovar-Vidales T, Roque R, Clark AF, Wordinger RJ (2008) Tissue transglutaminase expression and activity in normal and glaucomatous human trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci 49:622–628

    PubMed  Google Scholar 

  • Tovar-Vidales T, Clark AF, Wordinger RJ (2011) Transforming growth factor-beta2 utilizes the canonical Smad-signaling pathway to regulate tissue transglutaminase expression in human trabecular meshwork cells. Exp Eye Res 93:442–451

    Google Scholar 

  • Tripathi RC, Li JP, Borisuth NSC, Tripathi BJ (1993a) Trabecular cells of the eye express messenger RNA for transforming growth factor-β1 and secrete this cytokine. Invest Ophthalmol Vis Sci 34:2562–2569

    PubMed  CAS  Google Scholar 

  • Tripathi RC, Borisuth NS, Kolli SP, Tripathi BJ (1993b) Trabecular cells express receptors that bind TGF-β1 and TGF-β2: a qualitative and quantitative characterization. Invest Ophthalmol Vis Sci 34:260–263

    PubMed  CAS  Google Scholar 

  • Tripathi RC, Li J, Chan WFA, Tripathi BJ (1994a) Aqueous humor in glaucomatous eyes contains an increased level of TGF-β2. Exp Eye Res 58:723–727

    Google Scholar 

  • Tripathi RC, Chan WFA, Li J, Tripathi BJ (1994b) Trabecular cells express the TGF-β2 gene and secrete this cytokine. Exp Eye Res 58:523–528

    PubMed  CAS  Google Scholar 

  • Trivedi RH, Nutaitis M, Vroman D, Crosson CE (2011) Influence of race and age on aqueous humor levels of transforming growth factor-beta 2 in glaucomatous and nonglaucomatous eyes. J Ocul Pharmacol Ther 27:477–480

    PubMed  CAS  Google Scholar 

  • Varela HJ, Hernandez MR (1997) Astrocyte responses in human optic nerve head with primary open-angle glaucoma. J Glaucoma 6:303–313

    PubMed  CAS  Google Scholar 

  • Wallentin N, Wickstrom K, Lundberg C (1998) Effect of cataract surgery on aqueous TGF-beta and lens epithelial cell proliferation. Invest Ophthalmol Vis Sci 39:1410–1418

    PubMed  CAS  Google Scholar 

  • Wang S, Hirschberg R (2003) BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol 284:F1006–F1013

    PubMed  CAS  Google Scholar 

  • Wang S, Hirschberg R (2004) Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. J Biol Chem 279:23200–23206

    PubMed  CAS  Google Scholar 

  • Welge-Lüssen U, May CA, Lütjen-Drecoll E (2000) Induction of tissue transglutaminase in the trabecular meshwork by TGF-β1 and TGF-β2. Invest Ophthalmol Vis Sci 41:2229–2238

    PubMed  Google Scholar 

  • Wiederholt M, Thieme H, Stumpff F (2000) The regulation of trabecular meshwork and ciliary muscle contractility. Prog Retin Eye Res 19:271–295

    PubMed  CAS  Google Scholar 

  • Willis BC, Borok Z (2007) TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 293:L525–L534

    PubMed  CAS  Google Scholar 

  • Wordinger RJ, Agarwal R, Talati M, Fuller J, Lambert W, Clark AF (2002) Expression of bone morphogenetic proteins (BMP), BMP receptors, and BMP associated proteins in human trabecular meshwork and optic nerve head cells and tissues. Mol Vis 8:241–250

    PubMed  CAS  Google Scholar 

  • Wordinger RJ, Fleenor DL, Hellberg PE, Pang IH, Tovar TO, Zode GS, Fuller JA, Clark AF (2007) Effects of TGF-beta2, BMP-4, and gremlin in the trabecular meshwork: implications for glaucoma. Invest Ophthalmol Vis Sci 48:1191–1200

    PubMed  Google Scholar 

  • Wormstone IM, Tamiya S, Anderson I, Duncan G (2002) TGF-beta2-induced matrix modification and cell transdifferentiation in the human lens capsular bag. Invest Ophthalmol Vis Sci 43:2301–2308

    PubMed  Google Scholar 

  • Yamamoto N, Itonaga K, Marunouchi T, Majima K (2005) Concentration of transforming growth factor beta2 in aqueous humor. Ophthalmic Res 37:29–33

    PubMed  CAS  Google Scholar 

  • Yan X, Liu Z, Chen Y (2009) Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai) 41:263–272

    CAS  Google Scholar 

  • Yang Z, Mu Z, Dabovic B, Jurukovski V, Yu D, Sung J, Xiong X, Munger JS (2007) Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice. J Cell Biol 176:787–793

    PubMed  CAS  Google Scholar 

  • Ye H, Hernandez MR (1995) Heterogeneity of astrocytes in human optic nerve head. J Comp Neurol 362:441–452

    PubMed  CAS  Google Scholar 

  • Yoneda K, Nakano M, Mori K, Kinoshita S, Tashiro K (2007) Disease-related quantitation of TGF-beta3 in human aqueous humor. Growth Factors 25:160–167

    PubMed  CAS  Google Scholar 

  • Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968

    PubMed  CAS  Google Scholar 

  • Zhao X, Russell P (2005) Versican splice variants in human trabecular meshwork and ciliary muscle. Mol Vis 11:603–608

    PubMed  CAS  Google Scholar 

  • Zhao X, Ramsey KE, Stephan DA, Russell P (2004) Gene and protein expression changes in human trabecular meshwork cells treated with transforming growth factor-beta. Invest Ophthalmol Vis Sci 45:4023–4034

    PubMed  Google Scholar 

  • Zhou L, Maruyama I, Li Y, Cheng EL, Yue BY (1999) Expression of integrin receptors in the human trabecular meshwork. Curr Eye Res 19:395–402

    PubMed  Google Scholar 

  • Zode GS, Clark AF, Wordinger RJ (2009) Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation. Glia 57:755–766

    PubMed  Google Scholar 

  • Zode GS, Sethi A, Brun-Zinkernagel AM, Chang IF, Clark AF, Wordinger RJ (2011) Transforming growth factor-beta2 increases extracellular matrix proteins in optic nerve head cells via activation of the Smad signaling pathway. Mol Vis 17:1745–1758

    PubMed  CAS  Google Scholar 

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  1. Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany

    Rudolf Fuchshofer & Ernst R. Tamm

  2. Department of Anatomy, University of Regensburg, Universitätsstrasse 31, 93053, Regensburg, Germany

    Ernst R. Tamm

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Fuchshofer, R., Tamm, E.R. The role of TGF-β in the pathogenesis of primary open-angle glaucoma. Cell Tissue Res 347, 279–290 (2012). https://doi.org/10.1007/s00441-011-1274-7

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