| First Author | Fata JE | Year | 2001 |
| Journal | J Clin Invest | Volume | 108 |
| Issue | 6 | Pages | 831-41 |
| PubMed ID | 11560952 | Mgi Jnum | J:71690 |
| Mgi Id | MGI:2150569 | Doi | 10.1172/JCI13171 |
| Citation | Fata JE, et al. (2001) Accelerated apoptosis in the Timp-3-deficient mammary gland. J Clin Invest 108(6):831-41 |
| abstractText | 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. |
