title: Loss of PTEN expression by mouse fibroblasts results in lung fibrosis through a CCN2-dependent mechanism.
abstract: Elevated adhesive signaling promotes fibrosis. Protein phosphatase and tensin homologue (PTEN) dephosphorylates focal adhesion kinase and suppresses the activation of Akt and hence suppresses adhesive signaling. Loss of PTEN expression is associated with lung fibrosis, but whether PTEN expression by type I collagen-expressing cells controls lung fibrosis is unclear. Here, we use mice expressing tamoxifen-dependent cre recombinase expressed under the control of a COL1A2 promoter/enhancer and mice harboring floxed-PTEN and/or floxed-CCN2 alleles to assess whether loss of PTEN expression by type I collagen producing cells results in lung fibrosis in a CCN2-dependent fashion. In vivo, loss of PTEN expression resulted in the overexpression of both collagen type I and the pro-adhesive matricellular protein connective tissue growth factor (CTGF/CCN2). However, α-smooth muscle actin expression was unaffected. Loss of CCN2 expression by lung fibroblasts rescues this phenotype; i.e.., mice deficient in both PTEN and CCN2 in collagen type I-expressing cells do not develop significant collagen deposition in the lung. PTEN expression by collagen type I-expressing cells controls collagen deposition; therapeutic strategies blocking CCN2 may be of benefit in blocking excessive collagen deposition in fibrosis.
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1; Department of Ophthalmology, Lawson Health Research Institute, 268 Grosvenor Street, London, Ontario, Canada, N6A 4V2; Department of Pathology, Lawson Health Research Institute, 268 Grosvenor Street, London, Ontario, Canada, N6A 4V2.
authors: Sunil K
authors: SK
authors: Parapuram
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1.
authors: Katherine
authors: K
authors: Thompson
authors: Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1.
authors: Matthew
authors: M
authors: Tsang
authors: Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1.
authors: James
authors: J
authors: Hutchenreuther
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1.
authors: Christian
authors: C
authors: Bekking
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1.
authors: Shangxi
authors: S
authors: Liu
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1; Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Bldg., London, ON, Canada, N6A 5C1. Electronic address: Andrew.leask@schulich.uwo.ca.
authors: Andrew
authors: A
authors: Leask
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: CCN family; CCN2; Lung fibrosis; Matricellular proteins; PTEN; Scleroderma; ctgf