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PLOS ONE  2013 

The Effect of p38MAPK on Cyclic Stretch in Human Facial Hypertrophic Scar Fibroblast Differentiation

DOI: 10.1371/journal.pone.0075635

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Abstract:

Hypertrophic scars (HTS), the excessive deposition of scar tissue by fibroblasts, is one of the most common skin disorders. Fibroblasts derived from surgical scar tissue produce high levels of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1). However, the molecular mechanisms for this phenomenon is poorly understood. Thus, the purpose of this study was to evaluate the molecular mechanisms of HTS and their potential therapeutic implications. Fibroblasts derived from skin HTS were cultured and characterized in vitro. The fibroblasts were synchronized and randomly assigned to two groups: cyclic stretch and cyclic stretch pre-treated with SB203580 (a p38MAPK inhibitor). Cyclic stretch at 10% strain was applied at a loading frequency of 10 cycles per minute (i.e. 5 seconds of tension and 5 seconds of relaxation) for 0 h, 6 h and 12 h. Cyclic stretch on HTS fibroblasts led to an increase in the expression of α-SMA and TGF-β1 mRNA and protein and the phosphorylation of p38MAPK. SB203580 reversed these effects and caused a decrease in matrix contraction. Furthermore, HTS fibroblast growth was partially blocked by p38MAPK inhibition. Therefore, the mechanism of cyclic stretch involves p38 MAPK, and its inhibition is suggested as a novel therapeutic strategy for HTS.

References

[1]  Viera MH, Amini S, Valins W, Berman B (2010) Innovative therapies in the treatment of keloids and hypertrophic scars. J Clin Aesthet Dermatol 3: 20–26.
[2]  Larjava H, Wiebe C, Gallant-Behm C, Hart DA, Heino J, Hakkinen L (2011) Exploring scarless healing of oral soft tissues. J Can Dent Assoc 77: b18.
[3]  Guo L, Chen L, Bi S, Chai L, Wang Z, et al. (2012) PTEN inhibits proliferation and functions of hypertrophic scarHTS fibroblasts. Mol Cell Biochem 361: 161–168.
[4]  Butler PD, Longaker MT, Yang GP (2008) Current progress in keloid research and treatment. J Am Coll Surg 206: 731–741.
[5]  Honardoust D, Varkey M, Marcoux Y, Shankowsky HA, Tredget EE (2012) Reduced decorin, fibromodulin, and transforming growth factor-beta3 in deep dermis leads to hypertrophic scarring. J Burn Care Res 33: 218–227.
[6]  Ishiguro S, Akasaka Y, Kiguchi H, Suzuki T, Imaizumi R, et al. (2009) Basic fibroblast growth factor induces down-regulation of alpha-smooth muscle actin and reduction of myofibroblast areas in open skin wounds. Wound Repair Regen 17: 617–625.
[7]  Franz M, Spiegel K, Umbreit C, Richter P, Codina-Canet C, et al. (2009) Expression of Snail is associated with myofibroblast phenotype development in oral squamous cell carcinoma. Histochem Cell Biol 131: 651–660.
[8]  Varkey M, Ding J, Tredget EE (2011) Differential collagen-glycosaminoglycan matrix remodeling by superficial and deep dermal fibroblasts: potential therapeutic targets for hypertrophic scar. Biomaterials 32: 7581–7591.
[9]  Zunwen L, Shizhen Z, Dewu L, Yungui M, Pu N (2012) Effect of tetrandrine on the TGF-beta-induced smad signal transduction pathway in human hypertrophic scar fibroblasts in vitro. Burns 38: 404–413.
[10]  Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL (2007) TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. J Invest Dermatol 127: 2645–2655.
[11]  Armour A, Scott PG, Tredget EE (2007) Cellular and molecular pathology of HTS: basis for treatment. Wound Repair Regen 15 Suppl 1S6–17.
[12]  Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117: 557–567.
[13]  Ishida W, Mori Y, Lakos G, Sun L, Shan F, et al. (2006) Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J Invest Dermatol 126: 1733–1744.
[14]  Kawakita T, Espana EM, Higa K, et al. (2013) Activation of Smad-mediated TGF-β signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells. J Cell Physiol. 228: 225–234.
[15]  Ochicha O, Pringle JH, Mohammed AZ (2010) Immunohistochemical study of epithelial-myofibroblast interaction in Barrett metaplasia. Indian J Pathol Microbiol 53: 262–266.
[16]  Omori S, Kitagawa H, Koike J, Fujita H, Hida M, et al. (2008) Activated extracellular signal-regulated kinase correlates with cyst formation and transforming growth factor-beta expression in fetal obstructive uropathy. Kidney Int 73: 1031–1037.
[17]  Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453: 314–321.
[18]  Krane M, Dummler S, Dressen M, Hauner H, Hoffmann M, et al. (2011) Identification of an up-regulated anti-apoptotic network in the internal thoracic artery. Int J Cardiol 149: 221–226.
[19]  Nishimura K, Blume P, Ohgi S, Sumpio BE (2009) The effect of different frequencies of stretch on human dermal keratinocyte proliferation and survival. J Surg Res 155: 125–131.
[20]  Tan J, Peng X, Luo G, Ma B, Cao C, et al. (2010) Investigating the role of P311 in the hypertrophic scar. PLOS ONE 5: e9995.
[21]  Webb K, Hitchcock RW, Smeal RM, Li W, Gray SD, et al. (2006) Cyclic strain increases fibroblast proliferation, matrix accumulation, and elastic modulus of fibroblast-seeded polyurethane constructs. J Biomech 39: 1136–1144.
[22]  Nishimura K, Blume P, Ohgi S, Sumpio BE (2007) Effect of different frequencies of tensile strain on human dermal fibroblast proliferation and survival. Wound Repair Regen 15: 646–656.
[23]  Lee WL, Shyur LF (2012) Deoxyelephantopin impedes mammary adenocarcinoma cell motility by inhibiting calpain-mediated adhesion dynamics and inducing reactive oxygen species and aggresome formation. Free Radic Biol Med 52: 1423–1436.
[24]  Baryza MJ, Baryza GA (1995) The Vancouver Scar Scale: an administration tool and its interrater reliability. J Burn Care Rehabil 16: 535–538.
[25]  Cheng B, Liu HW, Fu XB, Sheng ZY, Li JF (2008) Coexistence and upregulation of three types of opioid receptors, mu, delta and kappa, in human hypertrophic scars. Br J Dermatol 158: 713–720.
[26]  Gilbert JA, Weinhold PS, Banes AJ, Link GW, Jones GL (1994) Strain profiles for circular cell culture plates containing flexible surfaces employed to mechanically deform cells in vitro. J Biomech 27: 1169–1177.
[27]  Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159.
[28]  Stuart K, Paderi J, Snyder PW, Freeman L, Panitch A (2011) Collagen-binding peptidoglycans inhibit MMP mediated collagen degradation and reduce dermal scarring. PLOS ONE 6: e22139.
[29]  Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199–210.
[30]  Hinz B, Dugina V, Ballestrem C, Wehrle-Haller B, Chaponnier C (2003) Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. Mol Biol Cell 14: 2508–2519.
[31]  Hinz B (2010) The myofibroblast: paradigm for a mechanically active cell. J Biomech 43: 146–155.
[32]  Wang J, Zohar R, McCulloch CA (2006) Multiple roles of alpha-smooth muscle actin in mechanotransduction. Exp Cell Res 312: 205–214.
[33]  Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol 87: 601–615.
[34]  Zhang Y, Dong C (2007) Regulatory mechanisms of mitogen-activated kinase signaling. Cell Mol Life Sci 64: 2771–2789.
[35]  Li Z, Li SR, Liu JY, Dai X, Tao L (2009) [To transdifferentiate human hypertrophic scar fibroblasts induced by connective tissue growth factor mediated transforming growth factor-beta 1 in vitro]. Zhonghua Shao Shang Za Zhi 25: 49–52.
[36]  Kamaraju AK, Roberts AB (2005) Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem 280: 1024–1036.
[37]  Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425: 577–584.
[38]  Kolosova I, Nethery D, Kern JA (2011) Role of Smad2/3 and p38 MAP kinase in TGF-beta1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol 226: 1248–1254.
[39]  Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 24: 5742–5750.
[40]  Yu L, Hebert MC, Zhang YE (2002) TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 21: 3749–3759.
[41]  Macfarlane SR, Sloss CM, Cameron P, Kanke T, McKenzie RC, et al. (2005) The role of intracellular Ca2+ in the regulation of proteinase-activated receptor-2 mediated nuclear factor kappa B signalling in keratinocytes. Br J Pharmacol 145: 535–544.
[42]  Huang C, Borchers CH, Schaller MD, Jacobson K (2004) Phosphorylation of paxillin by p38MAPK is involved in the neurite extension of PC-12 cells. J Cell Biol 164: 593–602.
[43]  Tsukada S, Westwick JK, Ikejima K, Sato N, Rippe RA (2005) SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells. J Biol Chem 280: 10055–10064.
[44]  Aarabi S, Longaker MT, Gurtner GC (2007) Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med 4: e234.
[45]  Paterno J, Vial IN, Wong VW, Rustad KC, Sorkin M, et al. (2011) Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation. Wound Repair Regen 19: 49–48.

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