Accelerated apoptosis in the Timp-3-deficient mammary gland

J Clin Invest. 2001 Sep;108(6):831-41. doi: 10.1172/JCI13171.


The proapoptotic proteinase inhibitor TIMP-3 is the only molecule of this family thought to influence cell death. We examined epithelial apoptosis in TIMP-3-deficient mice during mammary gland involution. Lactation was not affected by the absence of TIMP-3, but glandular function, as measured by gland-to-body weight ratio and production of beta-casein, was suppressed earlier during post-lactational involution than in controls. Histological examination revealed accelerated lumen collapse, alveolar-epithelial loss, and adipose reconstitution in Timp-3(-/-) females. Epithelial apoptosis peaked on the first day of involution in Timp-3-null glands but at day 3 in wild-type littermates. Unscheduled activation of gelatinase-A was evident by zymography and correlated with earlier fragmentation of fibronectin in Timp-3(-/-) mammary. To obtain independent evidence of the proapoptotic effects of TIMP-3 deficiency, we introduced recombinant TIMP-3-releasing pellets into regressing Timp-3(-/-) mammary tissue and showed that this treatment rescued lumen collapse and epithelial apoptosis. Ex vivo, involuting Timp-3(-/-) mammary tissue demonstrated accelerated epithelial apoptosis that could be reduced by metalloproteinase inhibition. The physiological relevance of TIMP-3 became apparent as Timp-3(-/-) dams failed to reestablish lactation after brief cessation of suckling. Thus, TIMP-3 is a critical epithelial survival factor during mammary gland involution.

Publication types

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

MeSH terms

  • Adipose Tissue / anatomy & histology
  • Animals
  • Apoptosis / physiology*
  • Culture Techniques
  • Enzyme Activation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Fibronectins / metabolism
  • Lactation / physiology
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / physiology
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Tissue Inhibitor of Metalloproteinase-3 / deficiency*
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / physiology*


  • Fibronectins
  • Tissue Inhibitor of Metalloproteinase-3
  • Matrix Metalloproteinase 2