Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema

Nature. 2003 Mar 13;422(6928):169-73. doi: 10.1038/nature01413.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Disease Progression
  • Disease Susceptibility
  • Gene Deletion
  • Humans
  • Inflammation / enzymology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Integrin beta Chains / genetics
  • Integrin beta Chains / metabolism
  • Integrins / genetics
  • Integrins / metabolism*
  • Macrophages, Alveolar / enzymology
  • Matrix Metalloproteinase 12
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Pulmonary Emphysema / enzymology
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Antigens, Neoplasm
  • Integrin beta Chains
  • Integrins
  • Transforming Growth Factor beta
  • integrin alphavbeta6
  • integrin beta6
  • Metalloendopeptidases
  • MMP12 protein, human
  • Matrix Metalloproteinase 12