Accelerated apoptosis in the Timp-3–deficient mammary gland
Jimmie E. Fata, Kevin J. Leco, Evelyn B. Voura, Hoi-Ying E. Yu, Paul Waterhouse, Gillian Murphy, Roger A. Moorehead, Rama Khokha
Jimmie E. Fata, Kevin J. Leco, Evelyn B. Voura, Hoi-Ying E. Yu, Paul Waterhouse, Gillian Murphy, Roger A. Moorehead, Rama Khokha
View: Text | PDF | Corrigendum
Article

Accelerated apoptosis in the Timp-3–deficient mammary gland

Abstract

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 β-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.

Authors

Jimmie E. Fata, Kevin J. Leco, Evelyn B. Voura, Hoi-Ying E. Yu, Paul Waterhouse, Gillian Murphy, Roger A. Moorehead, Rama Khokha

×

Figure 8

Options: View larger image (or click on image) Download as PowerPoint
After 2 days of involution, Timp-3–null female mice are unable to reinit...
After 2 days of involution, Timp-3–null female mice are unable to reinitiate lactation that is necessary for proper pup growth. Quantification of pup weight gain/loss when nursed by wild-type or Timp-3–null dams that have already undergone 2 days of involution. Pup weight was measured initially before placing with dams and every subsequent 24 hours. Percent weight gain/loss is calculated by subtracting original weight of pups (12 days of age) from the weight of the same pups at each time point. Weight loss was evident in pups placed with wild-type dams only for the first 3 days, but pup weights accelerated higher thereafter. In contrast, after 7 days, pups placed with Timp-3–null female mice failed to gain weight beyond their original weight. Quantification is representative of two separate experiments.