Regulation of Trophoblastic Gelatinases by Proto-oncogenes

Bischof, P.; Truong, Kelvin; Campana, A.

doi:10.1053/plac.2002.0890

Cited by 33 publications

(24 citation statements)

References 23 publications

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“…P , 0.01: **compared with control, þþcompared with EGF alone, ##compared with EGFþ U0126),^^compared with EGFþLY294002. Bischof et al 2003), possibly because of the presence of different promoter elements on the gelatinase genes (Huhtala et al 1991).…”

Section: Discussionmentioning

confidence: 99%

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

Qiu¹,

Yang²,

Tsang³

et al. 2004

Reproduction

146

113

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Epidermal growth factor (EGF) is present in the maternal-fetal environment and has an important role in placental development. Matrix metalloproteinase-9 (MMP-9) expression/activation is a pre-requisite in extravillous trophoblast invasion. Whereas EGF up-regulates MMP-9 activity in a variety of cell types, there is no direct evidence for the stimulation of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion by EGF in extravillous trophoblasts. In addition, the signalling pathways involved in this regulation are not clear. In the present study, we have examined the possible involvement of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in the regulation of the MMP-9/TIMP-1 system by EGF in vitro. We used a well-established invasive extravillous trophoblast cell line (HTR8/Svneo) and measured gene and protein expression by semi-quantitative RT-PCR and western analysis respectively. MMP activity was determined by zymography. We showed for the first time that EGF activated both PI3K/Akt and MAPK/extracellular-signal regulated kinase (ERK) signalling in HTR8/SVneo, and increased both MMP-9 and TIMP-1 mRNAs and protein concentrations. Interfering with either signalling pathway via PI3K inhibitor LY294002 or MEK inhibitor U0126 in EGF-stimulated HTR8/SVneo cells blocked the induction of MMP-9 and TIMP-1. LY294002 inhibited Akt phosphorylation, but had no effect on ERK phosphorylation; U0126 suppressed ERK phosphorylation without interfering with the phosphorylation of Akt. In addition, expression of constitutively active Akt (Myr-Akt1, Myr-Akt2, Myr-Akt3) was not sufficient to induce proMMP-9 and TIMP-1 secretion. Our results suggest that the activation of both PI3K and MAPK pathways in extravillous trophoblasts is necessary for the up-regulation of MMP-9 and TIMP-1 expression by EGF.

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Section: Discussionmentioning

confidence: 99%

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

Qiu¹,

Yang²,

Tsang³

et al. 2004

Reproduction

146

113

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“…6F,H,J,L,N,P), suggesting that there may be a compensatory increase in expression of MMP-9 by the TRAP-negative non-osteoclastic cells. The decreased expression of MMP-9 in c-Fos-/-growth plates may reflect the regulation of MMP-9 expression by c-Fos (Bischof et al, 2003). The normal expression of MMP-9, coupled with impaired endochondral ossification in the osteopetrotic mice, indicates that MMP-9 expression by non-osteoclasts is not sufficient to drive the ossification process normally and that another osteoclastic function is required for normal endochondral ossification.…”

Section: Research Articlementioning

confidence: 99%

Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

Ortéga

Wang

Ferrara

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Long bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9−/− growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9−/− phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9−/− growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.

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“…In human placentae, FOS, FOSB, FOSL1, and FOSL2 have been detected spatiotemporally at high levels in extravillous trophoblast cells (25)(26)(27). Moreover, AP-1 transcriptional activity is required for the promotion of MMP production by human trophoblast cells (28,29). However, the biological significance of individual FOS components in human trophoblast cells is not known.…”

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confidence: 99%

The FOS Transcription Factor Family Differentially Controls Trophoblast Migration and Invasion

Renaud

Kubota

Rumi

et al. 2014

Journal of Biological Chemistry

102

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Background: Trophoblast cells invade the uterus during pregnancy to promote blood flow to the conceptus. Results: The transcription factor FOS inhibits trophoblast invasion, whereas FOS-like (FOSL)-1 promotes invasion. Conclusion:The intracellular balance of FOS family transcription factors modulates trophoblast invasive potential. Significance: Understanding the regulation of trophoblast invasion is crucial for determining the etiology of several placentaassociated obstetrical complications.

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Regulation of Trophoblastic Gelatinases by Proto-oncogenes

Cited by 33 publications

References 23 publications

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

The FOS Transcription Factor Family Differentially Controls Trophoblast Migration and Invasion

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