Published ahead of print on September 22, 2005, doi:10.1164/rccm.200507-1058OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 1, January 2006, 112-121
A more recent version of this article appeared on January 1, 2006
Submitted on July 8, 2005
Accepted on September 20, 2005
Negative Regulation of Myofibroblast Differentiation by PTEN
Eric S White1*, Rachelle G Atrasz1, Biao Hu2, Sem H Phan2, Vuk Stambolic3, Tak W Mak3, Cory M Hogaboam2, Kevin R Flaherty1, Fernando J Martinez1, Christopher D Kontos4, and Galen B Toews1
1 Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, USA,
2 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA,
3 University of Toronto, University Health Network, Ontario Cancer Institute, Toronto, Ontario, Canada,
4 Division of Cardiology, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: docew{at}umich.edu.
Rationale: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis. Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.
Objective: To show that myofibroblast differentiation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity in vivo and to identify a potential mechanism by which this occurs. Methods: We utilized tissue sections of surgical lung biopsies from patients with idiopathic pulmonary fibrosis to localize expression of PTEN and  -SMA. We utilized cell culture of pten-/- and wild-type fibroblasts as well as adenoviral strategies and pharmacologic inhibitors to determine the mechanism by which PTEN inhibits -SMA, fibroblast proliferation, and collagen production.
Results: In human lung specimens of idiopathic pulmonary fibrosis, myofibroblasts within fibroblastic foci demonstrate diminished PTEN expression. Further, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten-/- fibroblasts, and in normal fibroblasts in which PTEN is inhibited, -SMA, proliferation, and collagen production is upregulated. Addition of transforming growth factor- to wild-type cells, but not pten-/- cells, results in increased -SMA expression in a time-dependent fashion. In pten-/- cells, reconstitution of PTEN decreases -SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibits transforming growth factor--induced myofibroblast differentiation. Both the protein and lipid phosphatase actions of PTEN are capable of modulating the myofibroblast phenotype.
Conclusions: The results indicate that in idiopathic pulmonary fibrosis, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.
Key words: myofibroblast; fibrosis; PTEN; phosphatase; smooth muscle actin
This article has been cited by other articles:
|
|
|
|
 
K. Vaahtomeri, E. Ventela, K. Laajanen, P. Katajisto, P.-J. Wipff, B. Hinz, T. Vallenius, M. Tiainen, and T. P. Makela
Lkb1 is required for TGF{beta}-mediated myofibroblast differentiation
J. Cell Sci.,
November 1, 2008;
121(21):
3531 - 3540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bu, B. Kapanadze, T. Hsu, and M. Trojanowska
Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-{beta}/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway
J. Biol. Chem.,
July 11, 2008;
283(28):
19593 - 19602.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Xia, D. Diebold, R. Nho, D. Perlman, J. Kleidon, J. Kahm, S. Avdulov, M. Peterson, J. Nerva, P. Bitterman, et al.
Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis
J. Exp. Med.,
July 7, 2008;
205(7):
1659 - 1672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Muro, F. A. Moretti, B. B. Moore, M. Yan, R. G. Atrasz, C. A. Wilke, K. R. Flaherty, F. J. Martinez, J. L. Tsui, D. Sheppard, et al.
An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis
Am. J. Respir. Crit. Care Med.,
March 15, 2008;
177(6):
638 - 645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. E.J. Teunissen, P. J.H. Smeets, P. H.M. Willemsen, L. J. De Windt, G. J. Van der Vusse, and M. Van Bilsen
Activation of PPAR{delta} inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts
Cardiovasc Res,
August 1, 2007;
75(3):
519 - 529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Pierce, K. Carpenter, C. Jakubzick, S. L. Kunkel, H. Evanoff, K. R. Flaherty, F. J. Martinez, G. B. Toews, and C. M. Hogaboam
Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21
Eur. Respir. J.,
June 1, 2007;
29(6):
1082 - 1093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Hinz, S. H. Phan, V. J. Thannickal, A. Galli, M.-L. Bochaton-Piallat, and G. Gabbiani
The Myofibroblast: One Function, Multiple Origins
Am. J. Pathol.,
June 1, 2007;
170(6):
1807 - 1816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. U. Wells and C. M. Hogaboam
Update in Diffuse Parenchymal Lung Disease 2006
Am. J. Respir. Crit. Care Med.,
April 1, 2007;
175(7):
655 - 660.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Pierce, K. Carpenter, C. Jakubzick, S. L. Kunkel, K. R. Flaherty, F. J. Martinez, and C. M. Hogaboam
Therapeutic Targeting of CC Ligand 21 or CC Chemokine Receptor 7 Abrogates Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary Fibroblasts to Immunodeficient Mice
Am. J. Pathol.,
April 1, 2007;
170(4):
1152 - 1164.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kuwano
PTEN as a New Agent in the Fight against Fibrogenesis
Am. J. Respir. Crit. Care Med.,
January 1, 2006;
173(1):
5 - 6.
[Full Text]
[PDF]
|
|
|
Copyright © 2005 American Thoracic Society
|
|
|
