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2077-038311202022Oct11Journal of clinical medicineJ Clin MedExpression Pattern of Tenascin-C, Matrilin-2, and Aggrecan in Diseases Affecting the Corneal Endothelium.599110.3390/jcm11205991Purpose: The aim of this study was to examine the expression pattern of tenascin-C, matrilin-2, and aggrecan in irreversible corneal endothelial pathology such as pseudophakic bullous keratopathy (PBK) and Fuchs’ endothelial corneal dystrophy (FECD), which most frequently require corneal transplantation. Materials and methods: Histological specimens of corneal buttons removed during keratoplasty were investigated in PBK (n = 20) and FECD (n = 9) and compared to healthy control corneas (n = 10). The sections were studied by chromogenic immunohistochemistry (CHR-IHC) and submitted for evaluation by two investigators. Semiquantitative scoring (0 to 3+) was applied according to standardized methods at high magnification (400x). Each layer of the cornea was investigated; in addition, the stroma was subdivided into anterior, middle, and posterior parts for more precise analysis. In case of non-parametric distribution Mann−Whitney test was applied to compare two groups. Kruskal−Wallis and Dunn’s multiple comparisons tests have been applied for comparison of the chromogenic IHC signal intensity among corneal layers within the control and patient groups. Differences of p < 0.05 were considered as significant. Results: Significantly elevated tenascin-C immunopositivity was present in the epithelium and every layer of the stroma in both pathologic conditions as compared to normal controls. In addition, also significantly stronger matrilin-2 positivity was detected in the epithelium; however, weaker reaction was present in the endothelium in PBK cases. Minimal, but significantly elevated immunopositivity could be observed in the anterior and posterior stroma in the FECD group. Additionally, minimally, but significantly higher aggrecan immunoreaction was present in the anterior stroma in PBK and in the posterior stroma in both endothelial disorders. All three antibodies disclosed the strongest reaction in the posterior stroma either in PBK or in FECD cases. Conclusions: These extracellular matrix molecules disclosed up to moderate immunopositivity in the corneal layers in varying extents. Through their networking, bridging, and adhesive abilities these proteins are involved in corneal regeneration and tissue reorganization in endothelial dysfunction.VarkolyGrétaGDepartment of Ophthalmology, Szabolcs-Szatmár-Bereg County Hospitals, 4400 Nyíregyháza, Hungary.HortobágyiTibor GTGAlbert Szent-Györgyi Medical School, University of Szeged, 6720 Szeged, Hungary.GebriEnikőEDepartment of Dentoalveolar Surgery and Dental Outpatient Care, Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary.BenczeJánosJ0000-0002-6357-0671Division of Radiology and Imaging Science, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.HortobágyiTiborT0000-0001-5732-7942Department of Neurology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.Institute of Psychiatry Psychology and Neuroscience, King's College London, London SE5 8AB, UK.Centre for Age-Related Medicine, Stavanger University Hospital, 4011 Stavanger, Norway.Institute of Neuropathology, University Hospital Zurich, 8091 Zurich, Switzerland.MódisLászlóLJrDepartment of Ophthalmology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.engÚNKP-22-2-INew National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation FundGrant No. KTIA_13_NAP-A-II/7; NKFIH_SNN_132999Hungarian Brain Research Program (NAP)Journal Article20221011
SwitzerlandJ Clin Med1016065882077-0383Fuchs’ dystrophyaggrecancorneaextracellular matrixmarilin-2pseudophakic bullous keratopathytenascin-CThe authors declare no conflict of interest.202291820221032022107202210271302022102860202210286120221011epublish36294311PMC960475210.3390/jcm11205991jcm11205991Michelacci Y.M. Collagens and proteoglycans of the corneal extracellular matrix. Braz. J. Med. Biol. Res. 2003;36:1037–1046. doi: 10.1590/S0100-879X2003000800009.10.1590/S0100-879X200300080000912886457Meek K.M., Fullwood N.J. Corneal and scleral collagens—A microscopist’s perspective. Micron. 2001;32:261–272. doi: 10.1016/S0968-4328(00)00041-X.10.1016/S0968-4328(00)00041-X11006506Puri S., Coulson-Thomas Y.M., Gesteira T.F., Coulson-Thomas V.J. Distribution and function of glycosaminoglycans and proteoglycans in the development, homeostasis and pathology of the ocular surface. Front. Cell Dev. Biol. 2020;8:731. doi: 10.3389/fcell.2020.00731.10.3389/fcell.2020.00731PMC743891032903857Scott J.E. Extracellular matrix, supramolecular organisation and shape. J. Anat. 1995;187:259–269.PMC11674227591990Esko J.D., Kimata K., Lindahl U. Proteoglycans and sulfated glycosaminoglycans. In: Varki A., Cummings R.D., Esco J.D., editors. Essentials of Glycobiology. 2nd ed. Cold Spring Harbor Laboratory Press; New York, NY, USA: 2009. p. 800.20301236Maurice D.M. The structure and transparency of the cornea. J. Physiol. 1957;136:263–286. doi: 10.1113/jphysiol.1957.sp005758.10.1113/jphysiol.1957.sp005758PMC135888813429485Módis L. Organization of the Extracellular Matrix: A Polarization Microscopic Approach. 1st ed. CRC Press; Boca Raton, FL, USA: 1991. Structure of the Corneal Stroma; pp. 124–130.Goldberg M.F., Ferguson T.A., Pepose J.S. Detection of cellular adhesion molecules in inflamed human corneas. Ophthalmology. 1994;101:161–168. doi: 10.1016/S0161-6420(94)31370-4.10.1016/S0161-6420(94)31370-48302550Nemeth G., Felszeghy S., Kenyeres A., Szentmary N., Berta A., Süveges I., Módis L. Cell adhesion molecules in stromal corneal dystrophies. Histol. Histopathol. 2008;23:945–952.18498069McKay T.B., Schlötzer-Schrehardt U., Pal-Ghosh S., Stepp M.A. Integrin: Basement membrane adhesion by corneal epithelial and endothelial cells. Exp. Eye Res. 2020;198:108–138. doi: 10.1016/j.exer.2020.108138.10.1016/j.exer.2020.108138PMC750880732712184Pouw A.E., Greiner M.A., Coussa R.G., Jiao C., Han I.C., Skeie J.M., Fingert J.H., Mullins R.F., Sohn E.H. Cell–matrix interactions in the eye: From cornea to choroid. Cells. 2021;10:687. doi: 10.3390/cells10030687.10.3390/cells10030687PMC800371433804633Mobaraki M., Abbasi R., Vandchali S.O., Ghaffari M., Moztarzadeh F., Mozafari M. Corneal repair and regeneration: Current concepts and future directions. Front. Bioeng. Biotechnol. 2019;7:135. doi: 10.3389/fbioe.2019.00135.10.3389/fbioe.2019.00135PMC657981731245365Midwood K.S., Chiquet M., Tucker R.P., Orend G. Tenascin-C at a glance. J. Cell Sci. 2016;129:4321–4327. doi: 10.1242/jcs.190546.10.1242/jcs.19054627875272Udalova I.A., Ruhmann M., Thomson S.J., Midwood K.S. Expression and immune function of tenascin-C. Crit. Rev. Immunol. 2011;31:115–145. doi: 10.1615/CritRevImmunol.v31.i2.30.10.1615/CritRevImmunol.v31.i2.3021542790Orend G., Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244:143–163. doi: 10.1016/j.canlet.2006.02.017.10.1016/j.canlet.2006.02.01716632194Wiemann S., Reinhard J., Faissner A. Immunomodulatory role of the extracellular matrix protein tenascin-C in neuroinflammation. Biochem. Soc. Trans. 2019;47:1651–1660. doi: 10.1042/BST20190081.10.1042/BST2019008131845742Chiquet-Ehrismann R., Tannheimer M., Koch M., Brunner A., Spring J., Martin D., Baumgartner S., Chiquet M. Tenascin-C expression by fibroblasts is elevated in stressed collagen gels. J. Cell Biol. 1994;127:2093–2101. doi: 10.1083/jcb.127.6.2093.10.1083/jcb.127.6.2093PMC21202877528751Deák F., Piecha D., Bachrati C., Paulsson M., Kiss I. Primary structure and expression of matrilin-2, the closest relative of cartilage matrix protein within the von Willebrand factor type A-like module superfamily. J. Biol. Chem. 1997;272:9268–9274. doi: 10.1074/jbc.272.14.9268.10.1074/jbc.272.14.92689083061Wagener R., Ehlen H.W., Ko Y.P., Kobbe B., Mann H.H., Sengle G., Paulsson M. The matrilins–adaptor proteins in the extracellular matrix. FEBS Lett. 2005;579:3323–3329. doi: 10.1016/j.febslet.2005.03.018.10.1016/j.febslet.2005.03.01815943978Wilson S.E., Torricelli A.A., Marino G.K. Corneal epithelial basement membrane: Structure, function and regeneration. Exp. Eye Res. 2020;194:108002. doi: 10.1016/j.exer.2020.108002.10.1016/j.exer.2020.108002PMC721774132179076Kiani C., Liwen C., Wu Y.J., Albert J.Y., Burton B.Y. Structure and function of aggrecan. Cell Res. 2002;12:19–32. doi: 10.1038/sj.cr.7290106.10.1038/sj.cr.729010611942407Roughley P.J., Mort J.S. The role of aggrecan in normal and osteoarthritic cartilage. J. Exp. Orthop. 2014;1:8. doi: 10.1186/s40634-014-0008-7.10.1186/s40634-014-0008-7PMC464883426914753Ghatak S., Maytin E.V., Mack J.A., Hascall V.C., Atanelishvili I., Rodriguez R.M., Markwald R.R., Misra S. Roles of proteoglycans and glycosaminoglycans in wound healing and fibrosis. Int. J. Cell Biol. 2015;2015:834893. doi: 10.1155/2015/834893.10.1155/2015/834893PMC458157826448760Bencze J., Szarka M., Bencs V., Szabó R.N., Módis L.V., Aarsland D., Hortobágyi T. Lemur tyrosine kinase 2 (LMTK2) level inversely correlates with phospho-tau in neuropathological stages of Alzheimer’s disease. Brain Sci. 2020;10:68. doi: 10.3390/brainsci10020068.10.3390/brainsci10020068PMC707147932012723Csonka T., Murnyák B., Szepesi R., Bencze J., Bognár L., Klekner Á., Hortobágyi T. Assessment of Candidate Immunohistochemical Prognostic Markers of Meningioma Recurrence. Folia Neuropathol. 2016;54:114–126. doi: 10.5114/fn.2016.60088.10.5114/fn.2016.6008827543769Tremble P., Chiquet-Ehrismann R., Werb Z. The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. Mol. Biol. Cell. 1994;5:439–453. doi: 10.1091/mbc.5.4.439.10.1091/mbc.5.4.439PMC3010537519905Ljubimov A.V., Saghizadeh M., Spirin K.S., Khin H.L., Lewin S.L., Zardi L., Bourdon M.A., Kenney M.C. Expression of tenascin-C splice variants in normal and bullous keratopathy human corneas. Investig. Ophthalmol. Vis. Sci. 1998;39:1135–1142.9620072Kenney M.C., Nesburn A.B., Burgeson R.E., Butkowski R.J., Ljubimov A.V. Abnormalities of the extracellular matrix in keratoconus corneas. Cornea. 1997;16:345–351. doi: 10.1097/00003226-199705000-00016.10.1097/00003226-199705000-000169143810Maseruka H., Bonshek R.E., Tullo A.B. Tenascin-C expression in normal, inflamed, and scarred human corneas. Br. J. Ophthalmol. 1997;81:677–682. doi: 10.1136/bjo.81.8.677.10.1136/bjo.81.8.677PMC17222819349157Sumioka T., Kitano A., Flanders K.C., Okada Y., Yamanaka O., Fujita N., Iwanishi H., Kao W.W., Saika S. Impaired cornea wound healing in a tenascin-C deficient mouse model. Lab. Investig. 2013;93:207–217. doi: 10.1038/labinvest.2012.157.10.1038/labinvest.2012.15723207449Szalai E., Felszeghy S., Hegyi Z., Módis L., Jr., Berta A., Kaarniranta K. Fibrillin-2, tenascin-C, matrilin-2, and matrilin-4 are strongly expressed in the epithelium of human granular and lattice type I corneal dystrophies. Mol. Vis. 2012;18:1927–1936.PMC341344222876117Akhtar S., Bron A.J., Hawksworth N.R., Bonshek R.E., Meek K.M. Ultrastructural morphology and expression of proteoglycans, big-H3, tenascin-C, fibrillin-1, and fibronectin in bullous keratopathy. Br. J. Ophthalmol. 2001;85:720–731. doi: 10.1136/bjo.85.6.720.10.1136/bjo.85.6.720PMC172400811371495Korpos É., Deák F., Kiss I. Matrilin-2, an extracellular adaptor protein, is needed for the regeneration of muscle, nerve and other tissues. Neural Regen. Res. 2015;10:866–869.PMC449833626199591Malin D., Sonnenberg-Riethmacher E., Guseva D., Wagener R., Aszódi A., Irintchev A., Riethmacher D. The extracellular-matrix protein matrilin 2 participates in peripheral nerve regeneration. J. Cell Sci. 2009;122:995–1004. doi: 10.1242/jcs.040378.10.1242/jcs.04037819295126Ichikawa T., Suenaga Y., Koda T., Ozaki T., Nakagawara A. ΔNp63/BMP-7-dependent expression of matrilin-2 is involved in keratinocyte migration in response to wounding. Biochem. Biophys. Res. Commun. 2008;369:994–1000. doi: 10.1016/j.bbrc.2008.02.128.10.1016/j.bbrc.2008.02.12818328806Sharma M.K., Watson M.A., Lyman M., Perry A., Aldape K.D., Deák F., Gutmann D.H. Matrilin-2 expression distinguishes clinically relevant subsets of pilocytic astrocytoma. Neurology. 2006;66:127–130. doi: 10.1212/01.wnl.0000188667.66646.1c.10.1212/01.wnl.0000188667.66646.1c16401863Torricelli A.A., Singh V., Santhiago M.R., Wilson S.E. The corneal epithelial basement membrane: Structure, function, and disease. Investig. Ophthalmol. Vis. Sci. 2013;54:6390–6400. doi: 10.1167/iovs.13-12547.10.1167/iovs.13-12547PMC378765924078382Jurkunas U.V., Bitar M., Rawe I. Colocalization of increased transforming growth factor-β-induced protein (TGFBIp) and clusterin in Fuchs endothelial corneal dystrophy. Investig. Ophthalmol. Vis. Sci. 2009;50:1129–1136. doi: 10.1167/iovs.08-2525.10.1167/iovs.08-2525PMC271955719011008Rada J.A., Thoft R.A., Hassell J.R. Increased aggrecan (cartilage proteoglycan) production in the sclera of myopic chicks. Dev. Biol. 1991;147:303–312. doi: 10.1016/0012-1606(91)90288-E.10.1016/0012-1606(91)90288-E1916012Bouhenni R., Hart M., Al-Jastaneiah S., AlKatan H., Edward D.P. Immunohistochemical expression and distribution of proteoglycans and collagens in sclerocornea. Int. Ophthalmol. 2013;33:691–700. doi: 10.1007/s10792-012-9710-6.10.1007/s10792-012-9710-623325424Wilson S.E. Corneal wound healing. Exp. Eye Res. 2020;197:108089. doi: 10.1016/j.exer.2020.108089.10.1016/j.exer.2020.108089PMC748342532553485Kenney M.C., Chwa M., Alba A., Saghizadeh M., Huang Z.S., Brown D.J. Localization of TIMP-1, TIMP-2, TIMP-3, gelatinase A and gelatinase B in pathological human corneas. Curr. Eye Res. 1998;17:238–246. doi: 10.1076/ceyr.17.3.238.5222.10.1076/ceyr.17.3.238.52229543631Nishida T., Inui M., Nomizu M. Peptide therapies for ocular surface disturbances based on fibronectin–integrin interactions. Prog. Retin. Eye Res. 2015;47:38–63. doi: 10.1016/j.preteyeres.2015.01.004.10.1016/j.preteyeres.2015.01.00425645519Zhou Y., Wang T., Wang Y., Meng F., Ying M., Han R., Hao P., Wang L., Li X. Blockade of extracellular high-mobility group box 1 attenuates inflammation-mediated damage and haze grade in mice with corneal wounds. Int. Immunopharmacol. 2020;83:106468. doi: 10.1016/j.intimp.2020.106468.10.1016/j.intimp.2020.10646832279044Dhaouadi S., Benabderrazek R., Erne W., Loustau T., Fayçal C.A., Ksouri A., Murdamoothoo D., Mörgelin M., Kungl A.J., Jung A. Novel human tenascin-C function-blocking camel single domain nanobodies. Front. Immunol. 2021;12:635166. doi: 10.3389/fimmu.2021.635166.10.3389/fimmu.2021.635166PMC800691833790905Gupta S., Fink M.K., Ghosh A., Tripathi R., Sinha P.R., Sharma A., Hesemann N.P., Chaurasia S.S., Giuliano E.A., Mohan R.R. Novel combination BMP7 and HGF gene therapy instigates selective myofibroblast apoptosis and reduces corneal haze in vivo. Investig. Ophthalmol. Vis. Sci. 2018;59:1045–1057. doi: 10.1167/iovs.17-23308.10.1167/iovs.17-23308PMC582274329490341Poleni P.E., Bianchi A., Etienne S., Koufany M., Sebillaud S., Netter P., Terlain B., Jouzeau J.Y. Agonists of peroxisome proliferators-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycans’ production in chondrocytes. Osteoarthr. Cartil. 2007;15:493–505. doi: 10.1016/j.joca.2006.10.009.10.1016/j.joca.2006.10.00917140817