Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors

Fata, Jimmie E.; Ho, Allen; Leco, Kevin J.; Moorehead, Roger A.; Khokha, Rama

doi:10.1007/s000180050500

Cited by 131 publications

(90 citation statements)

References 190 publications

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“…Accumulating experimental evidence indicates the MMPs are important mediators of the ovulatory process (Brannstrom et al 1988, Butler et al 1991. The relative abundance of MMPs vs their endogenous proteinase inhibitors (TIMPs) dictates net ECM deposition vs degradation (Fata et al 2000). Results of the present studies demonstrated that mRNA and protein for TIMP-3 and TIMP-4 were increased in bovine preovulatory follicles following the gonadotropin surge, suggestive of a potential role for both TIMPs in regulation of preovulatory MMP activity.…”

Section: Discussionsupporting

confidence: 48%

“…Since ovulation is a prerequisite for fertilization and embryonic development, the mechanism of ovulation has been a subject of investigation for some time. Experimental evidence supports the theory that proteolytic degradation of the extracellular matrix (ECM) at the apex of ovulatory follicles prior to ovulation is a crucial step in the complex cascade of events initiated by the LH surge (Fata et al 2000, Ny et al 2002. Matrix metalloproteinases (MMPs) or matrixins, together with their tissue inhibitors (TIMPs) regulate ECM remodeling during both physiological and pathological conditions (Vu & Werb 2000, Coussens et al 2002, Curry & Osteen 2003.…”

Section: Introductionmentioning

confidence: 91%

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Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

Bakke

Pursley

et al. 2004

Reproduction

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The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are potential regulators of the focalized extracellular matrix degradation required for ovulation. The objectives of the present study were to determine localization and temporal regulation of TIMP-3 and TIMP-4 mRNA and protein in bovine preovulatory follicles. Ovaries containing preovulatory follicles were collected at 0, 12 and 20 h after GnRH injection for real-time PCR quantification of TIMP-3 and TIMP-4 mRNAs and immunohistochemical localization studies. Additional samples collected at 0, 6, 12, 18 and 24 h post GnRH injection were subjected to Western analysis to determine temporal changes in TIMP-3 and TIMP-4 proteins in the apex and base of preovulatory follicles. Results indicate the gonadotropin surge regulates TIMP-3 and TIMP-4 expression. TIMP-3 and TIMP-4 mRNAs increased within 12 h after GnRH injection. TIMP-3 protein was localized to granulosal and thecal layers of preovulatory follicles and adjacent ovarian stroma, whereas TIMP-4 immunoreactivity was localized to granulosal and thecal cells and ovarian blood vessels. Amounts of TIMP-3 and TIMP-4 proteins in the follicular apex peaked within 12 h post GnRH injection and subsequently declined by 24 h. However, amounts of TIMP-3 and TIMP-4 proteins in the base were not elevated after GnRH administration. Results demonstrate that mRNA and protein for both TIMP-3 and TIMP-4 are increased in bovine preovulatory follicles following the gonadotropin surge. Coordinate expression of TIMPs and MMPs may help regulate the extracellular matrix remodeling characteristic of the ovulatory process.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 91%

Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

Bakke

Pursley

et al. 2004

Reproduction

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“…However, very low levels of MMPs were present in the gland, whereas TIMP-1 was upregulated, shifting the proteolytic balance in favor of inhibition. The second proteinase-dependent stage begins around day 3 of involution and is characterized by a decrease in lactogenic hormones, collapse of glandular structures, and basement membrane destruction, resulting in active tissue remodeling and irreversible loss of the differenciated functions of the mammary gland (9,11,12,18). This phase is characterized by upregulation of mRNA and activity for proteolytic enzymes, including gelatinases A and B and stromelysin-1, and downregulation of the inhibitor TIMP-1 (18).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Zaragozá

Gimeno²,

Miralles³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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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...

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“…A família ADAMTS, é geralmente subdividida em quatro classes, baseada nas similaridades estruturais e/ou funcionais: proteoglicanases (ADAMTS -1, -4, -5, -8, -e -15), pró-colagenases-n-peptidades ( ADAMTS -2, -3 e -14), clivagem do fator de Von Willebrand (ADAMTS-13), e aquelas proteases que as funções permanecem indefinidas (APTE, 2009;PORTER et al, 2005 Junto com o endométrio, a glândula mamária adulta é um órgão terminal, que é responsivo às flutuações hormonais no ciclo reprodutivo, e são remodeladas na expectativa de uma possível gravidez (FATA et al, 2000). …”

Section: Substratos Das Adamtss Proteasesunclassified

Influência do estrógeno, progesterona e testosterona nos níveis de expressão e na distribuição de ADAMTS-1 (uma desintegrina e metaloproteinase com domínios trombospondinas 1) em células mamárias humanas normais e tumorais.

Silva¹

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Gostaria de agradecer à Profa. Dra. Vanessa Morais Freitas, por todo apoio e orientação. Muito obrigada pela oportunidade, pela confiança, ensinamentos e pela SUPER PACIÊNCIA (que não foi pouca). Serei eternamente grata por você ter me recebido de braços abertos e aceito realizar este projeto comigo. Admiro muito sua inteligência e sua liderança. Sua postura profissional é um exemplo para mim. Muito obrigada! Agradeço ao Prof. Dr. Ruy Gastaldoni Jaeger, pela colaboração neste estudo, e por todas as sugestões feitas durante o processo de escrita do meu artigo, especialmente na formatação das figuras. Obrigada pela permissão em utilizar os equipamentos e reagentes do seu laboratório. O câncer de mama é segundo tipo de neoplasia mais frequente no mundo, e no Brasil é o segundo maior causador de morte entre as mulheres. Os hormônios sexuais estão dentre os vários fatores indutores ou promotores da carcinogênese. O microambiente tumoral está ligado ao desenvolvimento e a progressão do câncer. Ele é composto por fibroblastos, células inflamatórias, fatores de crescimento, proteínas, glicosaminoglicanos, proteoglicanos e proteases que remodelam a MEC. ADAMTS (uma desintegrina e metaloproteinase com domínios trombospondinas) é uma enzima dependente de Zn 2+ /Ca 2+ . Na literatura o papel da ADAMTS-1 no câncer não está claramente estabelecido, tanto sua alta expressão, quanto sua baixa expressão foram reportados em tumores, quando comparados ao tecido normal. Neste trabalho avaliamos a influência dos hormônios sexuais nos níveis de expressão e na localização da protease ADAMTS-1 em três linhagens celulares de mama. O qPCR demonstrou que a progesterona estimulou o aumento da expressão de mRNA de ADAMTS-1 nas células MCF-10A e nas células MDA-MB-231, o tratamento com estrógeno e progesterona estimulou a diminuição dos níveis desse mRNA. No Western blot, observamos nas linhagens MCF-10A e MCF-7 que os hormônios tendem a aumentar os níveis proteicos de ADAMTS-1, e que o estrógeno estimulou uma acentuada secreção de ADAMTS-1 na linhagem MCF-7. Na linhagem MDA-MB-231, os tratamentos com os hormônios demonstraram uma tendência a diminuir os níveis proteicos de ADAMTS-1 intracelular. Na imunofluorescência e no Western blot que analisou frações citoplasmáticas e nucleares, observamos a predominância de ADAMTS-1 no compartimento nuclear. Nossos resultados sugerem que 1) os hormônios regulam a expressão de ADAMTS-1 nas células normais e tumorais de mama e que esse efeito foi relacionado com a presença dos receptores para esses hormônios e 2) ADAMTS-1 está predominantemente presente no núcleo dessas células mamárias. Breast cancer is the second most common type of neoplasia in the world, and the second largest cause of death among women in Brazil. Sex hormones are one of the several cancer inducers or promoters. Tumor microenvironment is associated to development and cancer progression. It is composed by fibroblasts, inflammatory cells, growth factors, proteins, proteoglycans and remodeling ECM proteases. ADAMTS (a disintegrin and m...

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Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors

Cited by 131 publications

References 190 publications

Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

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

Influência do estrógeno, progesterona e testosterona nos níveis de expressão e na distribuição de ADAMTS-1 (uma desintegrina e metaloproteinase com domínios trombospondinas 1) em células mamárias humanas normais e tumorais.

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