Akt inhibition up-regulates MMP1 through a CCN2-dependent pathway in human dermal fibroblasts

被引:19
作者
Bujor, Andreea M. [1 ]
Nakerakanti, Sashidar [1 ]
Morris, Erin [1 ]
Hant, Faye N. [1 ]
Trojanowska, Maria [1 ]
机构
[1] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA
关键词
Akt; extracellular matrix; CCN2; MMP1; TISSUE GROWTH-FACTOR; HYPERTROPHIC SCAR FIBROBLASTS; HUMAN SKIN FIBROBLASTS; MATRIX-METALLOPROTEINASES; GENE-EXPRESSION; WOUND REPAIR; COLLAGENASE; PROTEIN; ERK; DIFFERENTIATION;
D O I
10.1111/j.1600-0625.2010.01065.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Akt is a key signalling molecule that was found to be down-regulated in chronic wounds. Akt blockade has dual antifibrotic effects in human dermal fibroblasts, by up-regulating matrix metalloproteinase 1 (MMP1) and down-regulating collagen gene expression (J Invest Dermatol 2008: 128: 1906). The aim of this study was to gain additional insights into the mechanism of MMP1 up-regulation following Akt blockade. As previous studies showed that CCN2 can be a positive regulator of MMP1, we examined the effects of Akt inhibition on CCN2 expression. Akt blockade using a specific pharmacological inhibitor and Akt siRNA resulted in a significant up-regulation of CCN2, which correlated with the increase in MMP1. The MMP1 up-regulation following Akt blockade was partially suppressed by CCN2 siRNA, suggesting that CCN2 is contributing to this effect. Additional experiments showed that CCN2 induces phosphorylation of ERK1/2, Ets1 and c-Jun. Consistent with the stimulatory role of ERK1/2/Ets1 in the expression of MMP1, the ERK1/2 inhibitor UO126 prevented the phosphorylation of ERK1/2 and Ets1 and completely abrogated the induction of MMP1 after CCN2 overexpression, while having no effect on c-Jun activation. Taken together these results establish CCN2 as a key regulator of MMP1 induction via activation of the ERK1/2/Ets1 pathway. Down-regulation of Akt signalling leads to inappropriate activation of the CCN2/MMP1 pathway that may contribute to the pathogenesis of chronic wounds. Coordinate expression of CCN2, Akt and MMP1 could be important for normal wound healing to occur. Thus, targeting these specific proteins may represent a promising approach to the therapy of dysregulated wound healing.
引用
收藏
页码:347 / 354
页数:8
相关论文
共 37 条
[1]   Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis [J].
Aarabi, Shahram ;
Bhatt, Kirit A. ;
Shi, Yubin ;
Paterno, Josemaria ;
Chang, Edward I. ;
Loh, Shang A. ;
Holmes, Jeffrey W. ;
Longaker, Michael T. ;
Yee, Herman ;
Gurtner, Geoffrey C. .
FASEB JOURNAL, 2007, 21 (12) :3250-3261
[2]   Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways [J].
Agarwal, Smita ;
Achari, Chandrani ;
Praveen, D. ;
Roy, Karnati R. ;
Reddy, Gorla Venkateswara ;
Reddanna, Pallu .
EXPERIMENTAL DERMATOLOGY, 2009, 18 (11) :939-946
[3]   Temporal activity of plasminogen activators and matrix metalloproteinases during cutaneous wound repair [J].
Arumugam, S ;
Jang, YC ;
Chen-Jensen, C ;
Gibran, NS ;
Isik, FF .
SURGERY, 1999, 125 (06) :587-593
[4]  
Barone EJ, 1998, PLAST RECONSTR SURG, V102, P1023, DOI 10.1097/00006534-199809040-00015
[5]  
Bu Shizhong, 2006, FASEB J, V20, P184
[6]   Akt blockade downregulates collagen and upregulates MMP1 in human dermal fibroblasts [J].
Bujor, Andreea M. ;
Pannu, Jaspreet ;
Bu, Shizhong ;
Smith, Edwin A. ;
Muise-Helmericks, Robin C. ;
Trojanowska, Maria .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2008, 128 (08) :1906-1914
[7]   The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts [J].
Chen, CC ;
Chen, NY ;
Lau, LF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (13) :10443-10452
[8]   Mediation of transforming growth factor-β1-stimulated matrix contraction by fibroblasts -: A role for connective tissue growth factor in contractile scarring [J].
Daniels, JT ;
Schultz, GS ;
Blalock, TD ;
Garrett, Q ;
Grotendorst, GR ;
Dean, NM ;
Khaw, PT .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 163 (05) :2043-2052
[9]   Gene expression profiles from hypertrophic scar fibroblasts before and after IL-6 stimulation [J].
Dasu, MRK ;
Hawkins, HK ;
Barrow, RE ;
Xue, H ;
Hemdon, DN .
JOURNAL OF PATHOLOGY, 2004, 202 (04) :476-485
[10]   Connective tissue growth factor: Structure-function relationships of a mosaic, multifunctional protein [J].
De Winter, Patricia ;
Leoni, Patricia ;
Abraham, David .
GROWTH FACTORS, 2008, 26 (02) :80-91