title: Transforming growth factor-β enhances matrix metalloproteinase-2 expression and activity through AKT in fibroblasts derived from angiofibromas in patients with tuberous sclerosis complex.
abstract: BACKGROUND
  Patients with tuberous sclerosis complex (TSC) develop fibrous tumours in the brain, skin, kidney, heart and lungs due to TSC1/2 mutations. In the skin, patients develop angiofibromas that have vascular and fibrotic components in which transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-2 are important.
  
  
  OBJECTIVE
  To investigate if the TGF-β axis and MMP-2 play an important role in the pathogenesis of TSC angiofibromas.
  
  
  METHODS
  Samples from TSC angiofibromas and normal skin were measured for expression of TGF-β and MMP-2 by immunohistochemistry and real-time polymerase chain reaction. Fibroblasts grown from TSC angiofibromas (TSC fibroblasts) were incubated with TGF-β. Expression of ERK, AKT and S6K was measured by Western blotting, and MMP-2 expression and activity were determined by enzyme-linked immunosorbent assay and gelatin zymography, respectively.
  
  
  RESULTS
  There was an increase in the expression of TGF-β and MMP-2 in TSC tumours compared with those in normal skin. The baseline expression of MMP-2 was increased in conditioned medium from TSC fibroblasts. In addition, TGF-β enhanced MMP-2 production and activity, which could be abrogated by pretreatment with an AKT inhibitor (LY294002) but not with rapamycin. Finally, there was a significant colocalization of TGF-β and MMP-2 in the TSC tumours.
  
  
  CONCLUSIONS
  There is an increase of MMP-2 as a result of TGF-β acting through AKT in TSC tumour cells. This regulation of the TGF-β-AKT-MMP-2 axis is independent of mammalian target of rapamycin (mTOR) signalling. In addition to targeting the mTOR pathway, targeting TGF-β simultaneously could block dysregulated tissue remodelling in TSC tumours.
authors.affiliation: Department of Dermatology, Kaohsiung Medical University College of Medicine and Graduate Institute of Medicine, Kaohsiung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.forename: C-H
authors.initials: CH
authors.lastname: Hong
authors.forename: H-S
authors.initials: HS
authors.lastname: Yu
authors.forename: G-S
authors.initials: GS
authors.lastname: Chen
authors.forename: K-C
authors.initials: KC
authors.lastname: Yang
mesh_terms: D018322:Angiofibroma / Q000150:complications / Q000201:enzymology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D014402:Tuberous Sclerosis / Q000150:complications / Q000201:enzymology*
chemical_list: D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2