References
Query Results -- Details
MGI Accession ID: MGI:3040752
J Number: J:89578
Other Accession IDs:
Title: Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema.
Authors: Morris DG; Huang X; Kaminski N; Wang Y; Shapiro SD; Dolganov G; Glick A; Sheppard D
Journal: Nature
Volume: 422
Issue: 6928
Date: 2003 Mar 13
Year: 2003
Pages: 169-73
Review Status: Peer Reviewed
Abstract:
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.
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