Abstract
Procollagen C-proteinase enhancer 1 (PCPE-1) has been characterized as a protein capable of enhancing the activity of bone morphogenetic protein 1/tolloid-like proteinases in the biosynthetic processing of C-propeptides from procollagens I–III. This processing step is thought necessary to the formation of collagen I–III monomers capable of forming fibrils. Thus, PCPE-1 is predicted to play an important role in scarring, as scar tissue is predominantly composed of fibrillar collagen. Corneal scarring is of great clinical importance, as it leads to loss of visual acuity and, in severe cases, blindness. Here, we investigate a possible role for PCPE-1 in corneal scarring. Although differences in corneal opacity associated with scarring following injury of Pcolce −/− and wild-type (WT) mice using full-thickness excision or alkali burn models of corneal injury were not grossly apparent, differences in procollagen I processing levels between Pcolce −/− and WT primary corneal keratocytes were consistent with a role for PCPE-1 in corneal collagen deposition. An unexpected finding was that neoangiogenesis, which follows alkali burn cornea injury, was strikingly increased in Pcolce −/− cornea, compared to WT. A series of aortic ring assays confirmed the anti-angiogenic effects of PCPE-1. Another unexpected finding was of abnormalities of epithelial basement membrane and of re-epithelialization following Pcolce −/− corneal injury. Thus, PCPE-1 appears to be of importance as an anti-angiogenic factor and in re-epithelialization following injury in cornea and perhaps in other tissues as well.
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Adar R, Kessler E, Goldberg B (1986) Evidence for a protein that enhances the activity of type I procollagen C-proteinase. Coll Relat Res 6:267–277
Baicu CF, Zhang Y, Van Laer AO, Renaud L, Zile MR, Bradshaw AD (2012) Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload. Am J Physiol Heart Circ Physiol 303:H234–H240
Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, D'Amico G, Jones DT, Vojnovic B, Hodivala-Dilke K (2012) Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7:89–104
Brodovsky SC, McCarty CA, Snibson G, Loughnan M, Sullivan L, Daniell M, Taylor HR (2000) Management of alkali burns : an 11-year retrospective review. Ophthalmology 107:1829–1835
Chen YT, Huang CW, Huang FC, Tseng SY, Tseng SH (2006) The cleavage plane of corneal epithelial adhesion complex in traumatic recurrent corneal erosion. Mol Vis 12:196–204
Comaish IF, Lawless MA (2002) Progressive post-LASIK keratectasia: biomechanical instability or chronic disease process? J Cataract Refract Surg 28:2206–2213
Fisher LW, Stubbs JT 3rd, Young MF (1995) Antisera and cDNA probes to human and certain animal model bone matrix noncollagenous proteins. Acta Orthop Scand Suppl 266:61–65
Francone OL, Ishida BY, de la Llera-Moya M, Royer L, Happe C, Zhu J, Chalkey RJ, Schaefer P, Cox C, Burlingame A, Kane JP, Rothblat GH (2011) Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels. J Lipid Res 52:1974–1983
Galiacy SD, Froment C, Mouton-Barbosa E, Erraud A, Chaoui K, Desjardins L, Monsarrat B, Malecaze F, Burlet-Schiltz O (2011) Deeper in the human cornea proteome using nanoLC-Orbitrap MS/MS: an improvement for future studies on cornea homeostasis and pathophysiology. J Proteome 75:81–92
Ge G, Fernandez CA, Moses MA, Greenspan DS (2007) Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor. Proc Natl Acad Sci U S A 104:10010–10015
Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV (2005) BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem 280:7080–7087
Hassoun E, Safrin M, Ziv H, Pri-Chen S, Kessler E (2016) Procollagen C-proteinase enhancer 1 (PCPE-1) as a plasma marker of muscle and liver fibrosis in mice. PLoS ONE 11:e0159606
Huang G, Zhang Y, Kim B, Ge G, Annis DS, Mosher DF, Greenspan DS (2009) Fibronectin binds and enhances the activity of bone morphogenetic protein 1. J Biol Chem 284:25879–25888
Ippolito DL, AbdulHameed MD, Tawa GJ, Baer CE, Permenter MG, McDyre BC, Dennis WE, Boyle MH, Hobbs CA, Streicker MA, Snowden BS, Lewis JA, Wallqvist A, Stallings JD (2016) Gene expression patterns associated with histopathology in toxic liver fibrosis. Toxicol Sci 149:67–88
Ishizaki M, Zhu G, Haseba T, Shafer SS, Kao WW (1993) Expression of collagen I, smooth muscle alpha-actin, and vimentin during the healing of alkali-burned and lacerated corneas. Invest Ophthalmol Vis Sci 34:3320–3328
Kanaki T, Morisaki N, Bujo H, Takahashi K, Ishii I, Saito Y (2000) The regulatory expression of procollagen COOH-terminal proteinase enhancer in the proliferation of vascular smooth muscle cells. Biochem Biophys Res Commun 270:1049–1054
Kanski JJ (1999) Clinical ophthalmology, 4th edn. Butterworth-Heinemann, Boston, pp 139–140
Kessler E, Mould AP, Hulmes DJ (1990) Procollagen type I C-proteinase enhancer is a naturally occurring connective tissue glycoprotein. Biochem Biophys Res Commun 173:81–86
Kessler-Icekson G, Schlesinger H, Freimann S, Kessler E (2006) Expression of procollagen C-proteinase enhancer-1 in the remodeling rat heart is stimulated by aldosterone. Int J Biochem Cell Biol 38:358–365
Li Z, Burns AR, Smith CW (2006a) Two waves of neutrophil emigration in response to corneal epithelial abrasion: distinct adhesion molecule requirements. Invest Ophthalmol Vis Sci 47:1947–1955
Li Z, Rumbaut RE, Burns AR, Smith CW (2006b) Platelet response to corneal abrasion is necessary for acute inflammation and efficient re-epithelialization. Invest Ophthalmol Vis Sci 47:4794–4802
Malecaze F, Massoudi D, Fournie P, Tricoire C, Cassagne M, Malbouyres M, Hulmes DJ, Moali C, Galiacy SD (2014) Upregulation of bone morphogenetic protein-1/mammalian tolloid and procollagen C-proteinase enhancer-1 in corneal scarring. Invest Ophthalmol Vis Sci 55:6712–6721
Massoudi D, Malecaze F, Soler V, Butterworth J, Erraud A, Fournie P, Koch M, Galiacy SD (2012) NC1 Long and NC3 short splice variants of type XII collagen are overexpressed during corneal scarring. Invest Ophthalmol Vis Sci 53:7246–7256
Masuda M, Igarashi H, Kano M, Yoshikura H (1998) Effects of procollagen C-proteinase enhancer protein on the growth of cultured rat fibroblasts revealed by an excisable retroviral vector. Cell Growth Differ 9:381–391
Moali C, Font B, Ruggiero F, Eichenberger D, Rousselle P, Francois V, Oldberg A, Bruckner-Tuderman L, Hulmes DJ (2005) Substrate-specific modulation of a multisubstrate proteinase. C-terminal processing of fibrillar procollagens is the only BMP-1-dependent activity to be enhanced by PCPE-1. J Biol Chem 280:24188–24194
Muir AM, Ren Y, Butz DH, Davis NA, Blank RD, Birk DE, Lee SJ, Rowe D, Feng JQ, Greenspan DS (2014) Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 23:3085–3101
Muir AM, Massoudi D, Nguyen N, Keene DR, Lee SJ, Birk DE, Davidson JM, Marinkovich MP, Greenspan DS (2016) BMP1-Like proteinases are essential to the structure and wound healing of skin. Matrix Biol 56:114–131
Newman AC, Nakatsu MN, Chou W, Gershon PD, Hughes CC (2011) The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 22:3791–3800
Nicosia RF, Zorzi P, Ligresti G, Morishita A, Aplin AC (2011) Paracrine regulation of angiogenesis by different cell types in the aorta ring model. Int J Dev Biol 55:447–453
Ogata I, Auster AS, Matsui A, Greenwel P, Geerts A, D'Amico T, Fujiwara K, Kessler E, Rojkind M (1997) Up-regulation of type I procollagen C-proteinase enhancer protein messenger RNA in rats with CCl4-induced liver fibrosis. Hepatology 26:611–617
Pappano WN, Steiglitz BM, Scott IC, Keene DR, Greenspan DS (2003) Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Mol Cell Biol 23:4428–4438
Pfister RR, Haddox JL, Sommers CI (1998) Injection of chemoattractants into normal cornea: a model of inflammation after alkali injury. Invest Ophthalmol Vis Sci 39:1744–1750
Rattenholl A, Pappano WN, Koch M, Keene DR, Kadler KE, Sasaki T, Timpl R, Burgeson RE, Greenspan DS, Bruckner-Tuderman L (2002) Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen. J Biol Chem 277:26372–26378
Salza R, Peysselon F, Chautard E, Faye C, Moschcovich L, Weiss T, Perrin-Cocon L, Lotteau V, Kessler E, Ricard-Blum S (2014) Extended interaction network of procollagen C-proteinase enhancer-1 in the extracellular matrix. Biochem J 457:137–149
Sotozono C, He J, Tei M, Honma Y, Kinoshita S (1999) Effect of metalloproteinase inhibitor on corneal cytokine expression after alkali injury. Invest Ophthalmol Vis Sci 40:2430–2434
St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202
Steiglitz BM, Keene DR, Greenspan DS (2002) PCOLCE2 Encodes a functional procollagen C-proteinase enhancer (PCPE2) that is a collagen-binding protein differing in distribution of expression and post-translational modification from the previously described PCPE1. J Biol Chem 277:49820–49830
Steiglitz BM, Kreider JM, Frankenburg EP, Pappano WN, Hoffman GG, Meganck JA, Liang X, Hook M, Birk DE, Goldstein SA, Greenspan DS (2006) Procollagen C proteinase enhancer 1 genes are important determinants of the mechanical properties and geometry of bone and the ultrastructure of connective tissues. Mol Cell Biol 26:238–249
Wong VW, You F, Januszyk M, Gurtner GC, Kuang AA (2014) Transcriptional profiling of rapamycin-treated fibroblasts from hypertrophic and keloid scars. Ann Plast Surg 72:711–719
Xu H, Acott TS, Wirtz MK (2000) Identification and expression of a novel type I procollagen C-proteinase enhancer protein gene from the glaucoma candidate region on 3q21-q24. Genomics 66:264–273
Yu L, Ruifrok WP, Meissner M, Bos EM, van Goor H, Sanjabi B, van der Harst P, Pitt B, Goldstein IJ, Koerts JA, van Veldhuisen DJ, Bank RA, van Gilst WH, Sillje HH, de Boer RA (2013) Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis. Circ Heart Fail 6:107–117
Acknowledgements
We thank Drew Roenneburg for advice and provision of antibodies for some of the immunohistochemical analyses. This work was supported by National Institute of Health grant R01AR047746 (to D. S. G.).
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Massoudi, D., Germer, C.J., Glisch, J.M. et al. Procollagen C-proteinase enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea. Cell Tissue Res 370, 461–476 (2017). https://doi.org/10.1007/s00441-017-2689-6
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DOI: https://doi.org/10.1007/s00441-017-2689-6