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Involvement of TGF-ß Receptor– and Integrin-Mediated Signaling Pathways in the Pathogenesis of Granular Corneal Dystrophy II

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Involvement of TGF-ß Receptor– and Integrin-Mediated Signaling Pathways in the Pathogenesis of Granular Corneal Dystrophy II Biochemistry and Molecular Biology Involvement of TGF-␤ Receptor– and Integrin-Mediated Signaling Pathways in the Pathogenesis of Granular Corneal Dystrophy II Seung-il Choi,1 Yeong-Min Yoo,2 Bong-Yoon Kim,1 Tae-im Kim,1 Hyun-ju Cho,1 So-yoen Ahn,1 Hyung Keun Lee,1 Hyun-Soo Cho,3 and Eung Kweon Kim1 PURPOSE. The purpose of this study was to elucidate the (Invest Ophthalmol Vis Sci. 2010;51:1832–1847) DOI: pathophysiological process in primary cultured corneal fibro- 10.1167/iovs.09-4149 blasts (PCFs) from normal subjects and granular corneal dys- trophy (GCD) II patients, by using cDNA microarrays. ranular corneal dystrophy II (GCD II) is a disorder char- METHODS. PCFs were isolated from the corneas of normal Gacterized by age-dependent progressive accumulation of subjects and GCD II patients who were heterozygous and protein deposits in the corneal epithelia and stroma, followed homozygous for the TGFBI R124H mutation. RNA was isolated by disruption of corneal transparency. GCD II is an autosomal from each sample, and gene expression profiles were analyzed dominant disorder caused by a point mutation (R124H) in the with a cDNA microarray consisting of approximately 29,000 transforming growth factor-␤-induced gene (TGFBI) on chro- genes. Cell adhesion assays were performed to confirm the mosome 5, region q31.1,2 TGFBI encodes a highly conserved functionality of the detected gene expression profiles. 683 amino acid protein (TGFBIp) that contains a secretary signal sequence and an Arg-Gly-Asp (RGD) motif that serves as RESULTS. Twofold differences were detected in the expression a ligand recognition site for integrins.1 TGFBIp is a component of 555 genes between wild-type and homozygous GCD II PCFs. of extracellular matrix (ECM) that mediates cell adhesion and Of these, 319 genes were upregulated, and 236 genes were migration by interacting with integrins.3–5 More recently, it has downregulated in the homozygous GCD II PCFs. The most been shown that loss of TGFBIp induces cell proliferation and abundant and consistent changes were observed in gene fam- spontaneous tumor development in TGFBI-knockout mice.6 ilies encoding signal transduction pathways involving the ␤ Thirty-eight different mutations in TGFBI are involved in TGF- receptor– and integrin-mediated signaling, cell differen- corneal dystrophies. Remarkably, different mutations cause tiation and proliferation, immune responses, cell adhesion, unique corneal dystrophy phenotypes, such as R124H in GCD extracellular matrix (ECM) proteolytic enzymes, cell cycle, II (also called Avellino corneal dystrophy), R124C in lattice cytoskeletal organization, mitochondrial energy metabolism, corneal dystrophy type I, R555W in granular corneal dystrophy collagen catabolism, response to wounding, response to oxi- type I, and R555Q in Thiel-Behnke corneal dystrophy.7 dative stress, and the ubiquitin-mediated proteasomal degrada- The cornea is an avascular tissue located in the anterior part tion pathway. Cell adhesion assays demonstrated that heterozy- of the eye and consists of five layers of tissue that serve as a gous and homozygous GCD II PCFs strongly attached to barrier to infection. The principal cell types of the cornea collagen-I, collagen-IV, fibronectin, and laminin, compared include corneal epithelial cells in the outer region, keratocytes with wild-type cells. in the middle region, and endothelial cells in the inner region. CONCLUSIONS. Alterations in the TGF-␤ receptor– and integrin- Keratocytes, also known as corneal fibroblasts, have a dendritic mediated signaling pathway may play a key role in GCD II morphology and produce keratan sulfate proteoglycans that pathophysiology. If the novel factors identified in this study are are necessary for the maintenance of the corneal structure and involved in GCD II pathogenesis, they could assist in designing physiology, particularly for the maintenance of corneal trans- further studies to elucidate specific mechanisms of this disease. parency.8,9 These cells are also responsible for the synthesis of collagen fibrils and the ECM and for stromal repair after injury or infection. TGFBIp plays a significant role in the health of the cornea. From the 1Corneal Dystrophy Research Institute, Department of 3 For example, increased production of TGFBIp by corneal fibro- Ophthalmology, College of Medicine, and the Department of Biology, blasts has been detected in areas of corneal injury,10 and College of Life Science and Biotechnology, Yonsei University, Seoul, 2 ablation of the corneal stroma by laser in situ keratomileusis Korea; and the Laboratory of Veterinary Biochemistry and Molecular 11,12 Biology, College of Veterinary Medicine, Chungbuk National Univer- (LASIK) in GCD II patients accelerates TGFBIp deposition. sity, Cheongju, Korea. Overexpression of mutant TGFBI induces apoptotic cell death 13 Supported by Grant A080320 from the Korea Healthcare Technol- in human corneal epithelial cells, and age-dependent retinal ogy R&D Project, Ministry for Health, Welfare, and Family Affairs, degeneration has been observed in transgenic mice that ex- Republic of Korea. press a mutant form of the human TGFBI.14 More recently, we Submitted for publication June 15, 2009; revised November 7, have reported that PCFs are most susceptible to oxidative 2009; accepted November 11, 2009. stress.15 However, the pathophysiological process underlying Disclosure: S. Choi, None; Y.-M. Yoo, None; B.-Y. Kim, None; T. GCD II has yet to be fully elucidated. To understand the Kim, None; H. Cho, None; S. Ahn, None; H.K. Lee, None; H.-S. Cho, None; E.K. Kim, None pathophysiology of GCD II, we used cDNA microarray analysis Corresponding author: Eung Kweon Kim, Severance Hospital, to identify differential gene expression profiles between ho- Yonsei University, College of Medicine, Department of Ophthalmol- mozygous GCD II and wild-type PCFs. We also tested the ability ogy, 134 Shinchon-dong, Seodaemun-ku, 120-752, Seoul, Korea; of these cells to adhere to various ECM proteins to confirm the [email protected]. functional relevance of the gene expression results. Investigative Ophthalmology & Visual Science, April 2010, Vol. 51, No. 4 1832 Copyright © Association for Research in Vision and Ophthalmology IOVS, April 2010, Vol. 51, No. 4 TGF-␤ Receptor– and Integrin-Mediated Signaling in GCD II 1833 TABLE 1. Pairs of GCD II and Normal Samples Normal Cornea Mean Heterozygous Mean Homozygous Mean Pair Sex/Age Age Sex/Age Age Sex/Age Age Use of Samples 1 F/20 F/37 F/13 Microarray RT-PCR Western blot Cell-adhesion assay 2 M/10 25.3 F/20 35.3 M/10 16.6 Microarray RT-PCR Cell-adhesion assay 3 M/45 F/49 F/27 Microarray Cell-adhesion assay MATERIALS AND METHODS DNA. The concentration of total RNA was determined by UV spectro- photometry (ND-1000 UV-Vis Spectrophotometer; Nanodrop Technol- Isolation and Culture of Primary ogies, Wilmington, DE). Two quality controls were used for each RNA Corneal Fibroblasts sample: (1) an A260/A280 ratio between 1.7 and 2.3; and (2) an elec- tropherogram showing two distinct ribosomal peaks corresponding to Wild-type (n ϭ 3), heterozygous (n ϭ 3), and homozygous (n ϭ 3) either 18S and 28S for eukaryotic RNA bands at a ratio of 28S/18S of primary human corneal fibroblasts were prepared by using a published Ͼ0.5 with minimal or no degradation. The arrays were scanned (Ge- method.15 Donor confidentiality was maintained according to the Dec- neChip Scanner 3000 7G; Affymetrix), raw signal intensities were laration of Helsinki, and the protocol was approved by Severance normalized (GeneChip Operating Software [GCOS] algorithm; Af- Hospital IRB Committee (CR04124), Yonsei University. GCD II was fymetrix), and the data were analyzed (Gene Chip DNA Analysis Soft- diagnosed by DNA sequencing analysis of TGFBI mutations. Age, sex, ware [GDAS], ver. 2.0 according to the Affymetrix GeneChip Expres- and diagnosis in the GCD II cases are shown in Table 1. After removal sion Analysis Technical Manual; http://www.affymetrix.com). We of the corneal button for penetrating keratoplasty, the remaining cor- detected a twofold change in differential gene expression between the neal rims were harvested for culture of the normal corneal fibroblast. normal and homozygous samples. For statistical data analysis, we used The medical records of the donors from the eye bank of Yonsei a two-tailed unpaired Student’s t-test (P Ͻ 0.05), to assess significant University Severance Hospital did not show any genetic or systemic differences between the two cell types. metabolic disease. The fibroblasts grown from the pieces of corneal rims were treated as normal ones. Genetic normality of the BIGH3 Reverse Transcription–Polymerase gene in normal primary corneal fibroblasts was determined by DNA Chain Reaction sequencing analysis. Table 1 presents information regarding the cor- neal fibroblasts used in these studies. For cDNA microarray analysis, six Two micrograms of total RNA was reverse transcribed into cDNA samples (normal sample pairs 1, 2, and 3; and homozygous sample (Superscript II reverse transcriptase; Invitrogen, Carlsbad, CA) and an pairs 1, 2, and 3) were analyzed, excluding the heterozygous sample. Oligo (dT) primer (Invitrogen). The cDNA was amplified by using For RT-PCR studies, the samples were prepared by pooling total RNA primers derived from the sequence of the selected differentially ex- from two samples (Table 1, pairs 1 and 2). The sample pairs 1 and 2 pressed genes, and ␤-actin expression was used as the control. Ampli- were used for Western blot analysis. For the cell adhesion
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