Retinoids induce MMP-9 expression through RARα during mammary gland remodeling

Abstract

Retinoic acid (RA) is a signaling molecule in the morphogenesis of the mammary gland, modulating the expression of matrix metalloproteinases (MMPs). The aim of this paper was to study the role of RA during weaning, which consists of three events: apoptosis of the secretory cells, degradation of the extracellular matrix, and adipogenesis. CRABP II and CRBP-1 carrier proteins increased significantly during weaning compared with lactating glands but reverted to control values after the litter resuckled. The effects of RA are mediated by the nuclear receptors RAR␣, RAR␤, RAR␥, and RXR␣, which underwent an increase in protein levels during weaning. In an attempt to elucidate the RAR␣-dependent signaling pathway, ChIP assays were performed. The results showed the binding of RAR␣ to the MMP-9 promoter after 24-and 72-h weaning together with its coactivator p300; this fact could be responsible for the increase found in MMP-9 mRNA and protein levels in these conditions. Expression of related MMPs (MMP-2 and MMP-3) was also increased during weaning. Using gelatine zymography, we observed a time-dependent increase in active forms of MMP-9 and MMP-2. On the other hand, the inhibitor of MMPs, TIMP-1, was almost undetectable at 24-and 72-h weaning by Western blot. The role of retinoids in matrix remodeling is reinforced by the fact that administration of an acute dose of retinol palmitate to control lactating rats also induces MMP-9 expression. This emphasizes the importance of retinoids in vivo to regulate mammary gland involution. mammary gland involution; matrix metalloproteinase-9; stromelysin-1; retinoic acid; retinoid acid receptor-␣; TO FEMALE MAMMALS, THE COST OF LACTATION is exorbitant compared with other physiological processes. Thus, to assure a good milk production, the lactating animal has developed several physiological changes that include hyperphagia, liver and mammary gland hypertrophy, increased cardiac output, and increased blood flow to the gland, which, together with widespread changes in the metabolism of different tissues, assure a sufficient supply of substrates to the gland for milk production.Few adult tissues exhibit extensive apoptosis under physiological conditions. These include the small intestine, adipose, uterus, ovary, and mammary gland (1, 9). After being weaned, the mammary gland is remodeled in preparation for the next pregnancy/lactation cycle through a complex cellular program.This weaning process has two phases. The first phase is reversible; it depends on p53 and is characterized by the disappearance of the physiological adaptations and by an increase in the number of apoptotic events in the epithelia of the lobulo-alveolar compartment (15, 33). The second phase is p53 independent; it is irreversible and includes a proteolytic degradation of the basement membrane and remodeling of the mammary gland. To achieve the latter events, two main families of extracellular matrix (ECM)-degrading proteinases are activated, matrix metalloproteinases (MMPs) and serine proteinases, that are involved...

Effect of all-trans retinoic acid on renal expressions of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with glomerulosclerosis

“…As we know, ATRA interacts specifically with the RARs and RXRs, and most of the retinoic acid receptor subtypes are expressed in kidney, especially RAR-α and RAR-β [28]. A study has shown that ATRA induced the expression of MMP-9 through RAR-α during mammary gland remodeling [29]. Little is known about the promotor elements involved in MMP-2 and TIMP-1 regulation by ATRA, but we assume that a direct action of retinoic acid receptors is operative here as well.…”

Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization

“…Chromatin from mammary tissue was fixed and immunoprecipitated as described previously. 3,38 The following antibodies from Santa Cruz Biotechnology (Santa Cruz, CA, USA) were used: p65 (sc-109), p300 (sc-585) and RNA pol II (sc-899). After DNA purification, Input, Immunoprecipitated and Unrelated Ab fractions were analyzed by PCR with specific primers for either Real-time quantitative PCR (RT-qPCR) analysis and reverse transcriptase (RT)-PCR.…”

Vitamin A deficiency disturbs collagen IV and laminin composition and decreases matrix metalloproteinase concentrations in rat lung. Partial reversibility by retinoic acid

“…Alternatively, the response of the proteolytic status to VAD might be tissue specific. One fact favours this possibility: opposing results have been reported on the effect of RA in the expressions of MMP2 and 9 by different cell types in culture or tissues in vivo [41][42][43][44].…”