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High temperature requirement factor A1 (HTRA1) regulates the activation of latent TGF-β1 in keloid fibroblasts
Corresponding Author(s) : Shu Guo
Cellular and Molecular Biology,
Vol. 64 No. 1: Issue 1
Abstract
Scar treatments are considered a major issue in the plastic surgery field. Activation of the transforming growth factor-β (TGF-β)-mediated signaling pathway plays a key role in the scar pathogeneses, and high temperature requirement factor A1 (HTRA1) inhibits TGF-β1 activation in tumor cells. Our study aims to investigate the role of HTRA1 in the pathogenesis of scars. The mRNA levels of HTRA1 was evaluated by real time PCR, HTRA1 protein expression was determined using western blot and immunohistochemistry, and a luciferase assay was applied to measure dynamic changes of TGF-β1 activity. We found that the expression of HTRA1 was significantly elevated in keloid tissues, compared to normal skin, and TGF-β1 mRNA levels slightly increase in the keloid tissue. Furthermore, active TGF-β1 protein levels and Smad2 phosphorylation significantly increased in the keloid tissue. Treatment with the latent TGF-β1 or recombinant human HTRA1 (rhHTRA1), alone or in combination, increased Smad2 phosphorylation levels in keloid fibroblasts and active TGF-β1 contents of associated supernatants. Our results suggest that HTRA1 is involved in the pathogenesis of scars through regulating activation of latent TGF-β1 in keloid fibroblasts, and our study reveals that HTRA1 is a novel target that regulates scar formation.
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- References
- Arno AI, Gauglitz GG, Barret JP, Jeschke MG. Up-to-date approach to manage keloids and hypertrophic scars: A useful guide. Burns 2014; 40:1255-1266.
- Mori R, Tanaka K, de Kerckhove M, Okamoto M, Kashiyama K, Tanaka K, et al. Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring. Am J Pathol 2014; 184:2465-2479.
- Naylor MC, Brissett AE. Current concepts in the etiology and treatment of keloids. Facial Plast Surg 2012; 28:504-512.
- Ding J, Kwan P, Ma Z, Iwashina T, Wang J, Shankowsky HA, et al. Synergistic effect of vitamin D and low concentration of transforming growth factor beta 1, a potential role in dermal wound healing. Burns 2016; 42:1277-1286.
- Choi K, Lee K, Ryu SW, Im M, Kook KH, Choi C. Pirfenidone inhibits transforming growth factor-beta1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19. Mol Vis 2012; 18:1010-1020.
- Dong X, Zhang C, Ma S, Wen H. Mast cell chymase in keloid induces profibrotic response via transforming growth factor-beta1/Smad activation in keloid fibroblasts. Int J Clin Exp Pathol 2014; 7:3596-3607.
- Hsieh HL, Wang HH, Wu WB, Chu PJ, Yang CM. Transforming growth factor-beta1 induces matrix metalloproteinase-9 and cell migration in astrocytes: Roles of ROS-dependent ERK- and JNK-NF-kappaB pathways. J Neuroinflammation 2010; 7:88.
- Li Z, Choo-Wing R, Sun H, Sureshbabu A, Sakurai R, Rehan VK, et al. A potential role of the JNK pathway in hyperoxia-induced cell death, myofibroblast transdifferentiation and TGF-beta1-mediated injury in the developing murine lung. BMC Cell Biol 2011; 12:54.
- Murwantoko, Yano M, Ueta Y, Murasaki A, Kanda H, Oka C, et al. Binding of proteins to the PDZ domain regulates proteolytic activity of HtrA1 serine protease. Biochem J 2004; 381:895-904.
- Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 2000; 267:5699-5710.
- Launay S, Maubert E, Lebeurrier N, Tennstaedt A, Campioni M, Docagne F, et al. HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival. Cell Death Differ 2008; 15:1408-1416.
- Beaufort N, Scharrer E, Kremmer E, Lux V, Ehrmann M, Huber R, et al. Cerebral small vessel disease-related protease HtrA1 processes latent TGF-beta binding protein 1 and facilitates TGF-beta signaling. Proc Natl Acad Sci U S A 2014; 111:16496-16501.
- O'Leary R, Wood EJ, Guillou PJ. Pathological scarring: Strategic interventions. Eur J Surg 2002; 168:523-534.
- Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993; 48:959-966.
- Omori K, Hattori N, Senoo T, Takayama Y, Masuda T, Nakashima T, et al. Inhibition of plasminogen activator inhibitor-1 attenuates transforming growth Factor-beta-Dependent epithelial mesenchymal transition and differentiation of fibroblasts to myofibroblasts. PLoS One 2016; 11:e148969.
- Schmidt N, Irle I, Ripkens K, Lux V, Nelles J, Johannes C, et al. Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC Cancer 2016; 16:399.
- Glanz S, Mirsaidi A, Lopez-Fagundo C, Filliat G, Tiaden AN, Richards PJ. Loss-of-Function of HtrA1 abrogates All-Trans retinoic Acid-Induced osteogenic differentiation of mouse Adipose-Derived stromal cells through deficiencies in p70S6K activation. Stem Cells Dev 2016; 25:687-698.
- Li R, Zhang Q. HtrA1 may regulate the osteogenic differentiation of human periodontal ligament cells by TGF-beta1. J Mol Histol 2015; 46:137-144.
- Ng TK, Liang XY, Lai TY, Ma L, Tam PO, Wang JX, et al. HTRA1 promoter variant differentiates polypoidal choroidal vasculopathy from exudative age-related macular degeneration. Sci Rep 2016; 6:28639.
- Tsuchiya A, Yano M, Tocharus J, Kojima H, Fukumoto M, Kawaichi M, et al. Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. Bone 2005; 37:323-336.
- Grau S, Richards PJ, Kerr B, Hughes C, Caterson B, Williams AS, et al. The role of human HtrA1 in arthritic disease. J Biol Chem 2006; 281:6124-6129.
- Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, et al. HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development 2004; 131:1041-1053.
- Graham JR, Chamberland A, Lin Q, Li XJ, Dai D, Zeng W, et al. Serine protease HTRA1 antagonizes transforming growth factor-beta signaling by cleaving its receptors and loss of HTRA1 in vivo enhances bone formation. PLoS One 2013; 8:e74094.
- Samarakoon R, Higgins CE, Higgins SP, Kutz SM, Higgins PJ. Plasminogen activator inhibitor type-1 gene expression and induced migration in TGF-beta1-stimulated smooth muscle cells is pp60(c-src)/MEK-dependent. J Cell Physiol 2005; 204:236-246.
- Dennler S, Itoh S, Vivien D, Ten DP, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17:3091-3100.
References
References
Arno AI, Gauglitz GG, Barret JP, Jeschke MG. Up-to-date approach to manage keloids and hypertrophic scars: A useful guide. Burns 2014; 40:1255-1266.
Mori R, Tanaka K, de Kerckhove M, Okamoto M, Kashiyama K, Tanaka K, et al. Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring. Am J Pathol 2014; 184:2465-2479.
Naylor MC, Brissett AE. Current concepts in the etiology and treatment of keloids. Facial Plast Surg 2012; 28:504-512.
Ding J, Kwan P, Ma Z, Iwashina T, Wang J, Shankowsky HA, et al. Synergistic effect of vitamin D and low concentration of transforming growth factor beta 1, a potential role in dermal wound healing. Burns 2016; 42:1277-1286.
Choi K, Lee K, Ryu SW, Im M, Kook KH, Choi C. Pirfenidone inhibits transforming growth factor-beta1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19. Mol Vis 2012; 18:1010-1020.
Dong X, Zhang C, Ma S, Wen H. Mast cell chymase in keloid induces profibrotic response via transforming growth factor-beta1/Smad activation in keloid fibroblasts. Int J Clin Exp Pathol 2014; 7:3596-3607.
Hsieh HL, Wang HH, Wu WB, Chu PJ, Yang CM. Transforming growth factor-beta1 induces matrix metalloproteinase-9 and cell migration in astrocytes: Roles of ROS-dependent ERK- and JNK-NF-kappaB pathways. J Neuroinflammation 2010; 7:88.
Li Z, Choo-Wing R, Sun H, Sureshbabu A, Sakurai R, Rehan VK, et al. A potential role of the JNK pathway in hyperoxia-induced cell death, myofibroblast transdifferentiation and TGF-beta1-mediated injury in the developing murine lung. BMC Cell Biol 2011; 12:54.
Murwantoko, Yano M, Ueta Y, Murasaki A, Kanda H, Oka C, et al. Binding of proteins to the PDZ domain regulates proteolytic activity of HtrA1 serine protease. Biochem J 2004; 381:895-904.
Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 2000; 267:5699-5710.
Launay S, Maubert E, Lebeurrier N, Tennstaedt A, Campioni M, Docagne F, et al. HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival. Cell Death Differ 2008; 15:1408-1416.
Beaufort N, Scharrer E, Kremmer E, Lux V, Ehrmann M, Huber R, et al. Cerebral small vessel disease-related protease HtrA1 processes latent TGF-beta binding protein 1 and facilitates TGF-beta signaling. Proc Natl Acad Sci U S A 2014; 111:16496-16501.
O'Leary R, Wood EJ, Guillou PJ. Pathological scarring: Strategic interventions. Eur J Surg 2002; 168:523-534.
Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993; 48:959-966.
Omori K, Hattori N, Senoo T, Takayama Y, Masuda T, Nakashima T, et al. Inhibition of plasminogen activator inhibitor-1 attenuates transforming growth Factor-beta-Dependent epithelial mesenchymal transition and differentiation of fibroblasts to myofibroblasts. PLoS One 2016; 11:e148969.
Schmidt N, Irle I, Ripkens K, Lux V, Nelles J, Johannes C, et al. Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC Cancer 2016; 16:399.
Glanz S, Mirsaidi A, Lopez-Fagundo C, Filliat G, Tiaden AN, Richards PJ. Loss-of-Function of HtrA1 abrogates All-Trans retinoic Acid-Induced osteogenic differentiation of mouse Adipose-Derived stromal cells through deficiencies in p70S6K activation. Stem Cells Dev 2016; 25:687-698.
Li R, Zhang Q. HtrA1 may regulate the osteogenic differentiation of human periodontal ligament cells by TGF-beta1. J Mol Histol 2015; 46:137-144.
Ng TK, Liang XY, Lai TY, Ma L, Tam PO, Wang JX, et al. HTRA1 promoter variant differentiates polypoidal choroidal vasculopathy from exudative age-related macular degeneration. Sci Rep 2016; 6:28639.
Tsuchiya A, Yano M, Tocharus J, Kojima H, Fukumoto M, Kawaichi M, et al. Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. Bone 2005; 37:323-336.
Grau S, Richards PJ, Kerr B, Hughes C, Caterson B, Williams AS, et al. The role of human HtrA1 in arthritic disease. J Biol Chem 2006; 281:6124-6129.
Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, et al. HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development 2004; 131:1041-1053.
Graham JR, Chamberland A, Lin Q, Li XJ, Dai D, Zeng W, et al. Serine protease HTRA1 antagonizes transforming growth factor-beta signaling by cleaving its receptors and loss of HTRA1 in vivo enhances bone formation. PLoS One 2013; 8:e74094.
Samarakoon R, Higgins CE, Higgins SP, Kutz SM, Higgins PJ. Plasminogen activator inhibitor type-1 gene expression and induced migration in TGF-beta1-stimulated smooth muscle cells is pp60(c-src)/MEK-dependent. J Cell Physiol 2005; 204:236-246.
Dennler S, Itoh S, Vivien D, Ten DP, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17:3091-3100.