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.
Objectives: 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.
© 2010 The Authors. BJD © 2010 British Association of Dermatologists.