| First Author | Morris DG | Year | 2003 |
| Journal | Nature | Volume | 422 |
| Issue | 6928 | Pages | 169-73 |
| PubMed ID | 12634787 | Mgi Jnum | J:89578 |
| Mgi Id | MGI:3040752 | Doi | 10.1038/nature01413 |
| Citation | Morris DG, et al. (2003) Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422(6928):169-73 |
| abstractText | Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alpha(v)beta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease. |
