Akt inhibition up‐regulates MMP1 through a CCN2‐dependent pathway in human dermal fibroblasts
- 12 March 2010
- journal article
- Published by Wiley in Experimental Dermatology
- Vol. 19 (4), 347-354
- https://doi.org/10.1111/j.1600-0625.2010.01065.x
Abstract
Please cite this article as: Akt inhibition up‐regulates MMP1 through a CCN2‐dependent pathway in human dermal fibroblasts. Experimental Dermatology 2010. 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.Keywords
This publication has 38 references indexed in Scilit:
- Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf–Mediated PathwayMolecular Biology of the Cell, 2008
- PTEN: a promising pharmacological target to enhance epithelial wound healingBritish Journal of Pharmacology, 2007
- Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor ReceptorOnline Journal of Public Health Informatics, 2004
- Bisperoxovanadium compounds are potent PTEN inhibitorsFEBS Letters, 2004
- TGF-β and CTGF have overlapping and distinct fibrogenic effects on human renal cellsAmerican Journal of Physiology-Renal Physiology, 2002
- Randomised Double-blind Placebo Controlled Trial of Topical Autologous Platelet Lysate in Venous Ulcer HealingEuropean Journal of Vascular and Endovascular Surgery, 2000
- Temporal activity of plasminogen activators and matrix metalloproteinases during cutaneous wound repairSurgery, 1999
- Interleukin-1α and Collagenase Activity Are Elevated in Chronic WoundsPlastic and Reconstructive Surgery, 1998
- Enhancement of Fibroblast Collagenase (Matrix Metalloproteinase-1)Gene Expression by Ceramide Is Mediated by Extracellular Signal-regulated and Stress-activated Protein Kinase PathwaysOnline Journal of Public Health Informatics, 1998
- Matrix Metalloproteinases, Gelatinase and Collagenase, in Chronic Leg UlcersJournal of Investigative Dermatology, 1996