Accelerated apoptosis in the Timp-3-deficient mammary gland.
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.
Fata
J E
JE
Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada.
Leco
K J
KJ
Voura
E B
EB
Yu
H Y
HY
Waterhouse
P
P
Murphy
G
G
Moorehead
R A
RA
Khokha
R
R
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D046508:Culture Techniques; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D005353:Fibronectins; D019717:Tissue Inhibitor of Metalloproteinase-3; D020778:Matrix Metalloproteinase 2