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Accelerated apoptosis in the Timp-3-deficient mammary gland

Journal of Clinical Investigation, ISSN: 0021-9738, Vol: 108, Issue: 6, Page: 831-841
2001
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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 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.

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