Effects of combined treatment with fermented soybean (natto) intake and exercise on bone metabolism in ovariectomized rats.

OBJECTIVES: Using ovariectomized rats, we examined the influence of combined exercise tolerance and natto intake on the bone loss inhibitory effect. METHODS: We divided female Wistar rats into the following groups: Ovariectomy, Ovariectomy + Exercise, Ovariectomy + Natto Intake, Ovariectomy + Exercise + Natto Intake, and Pseudo-operative (Sham group). After conducting experiments on each group, we collected the tissues and performed morphological and molecular biological analyses. RESULTS: In comparison with the Ovariectomy group, only in the Ovariectomy + Exercise group was there a significant bone loss inhibitory effect in the femoral cancellous bone. Although there was a tendency toward this trend seen in the Natto Intake and Exercise + Natto Intake groups, these differences were not significant. The increase in messenger RNA expression levels of alkaline phosphatase (osteoblast marker) in the bone marrow caused by ovariectomy was suppressed by individual factors, and by those in combination. However, messenger RNA expression levels of estrogen receptor alpha in the bone marrow showed a decreasing tendency with each factor, and decreased significantly with the combination, similar to the Sham group. CONCLUSION: This suggests that natto intake and exercise maintain bone mass by different molecular mechanisms and that these two factors do not simply act synergistically in combination to maintain bone mass.

Peroxisome proliferator-activated receptor α mediates di-(2-ethylhexyl) phthalate transgenerational repression of ovarian Esr1 expression in female mice.

Di-(2-ethylhexyl)-phthalate (DEHP) is a phthalate ester that binds peroxisome proliferator-activated receptor α (PPARα) to induce proliferation of peroxisomes and regulate the expression of specific target genes. The question of whether the effect of DEHP on female reproductive processes is mediated via PPARα-dependent signaling is controversial. In this study, we investigated the effect of exposure to DEHP on ovarian expression of estrogen receptor α (Esr1) and aromatase (Cyp19a1) in three generations of Sv/129 wild-type (WT, +/+) and PPARα (-/-) knockout mice. Compared with untreated controls, ovarian expression of Esr1 decreased in response to DEHP treatment in the F0 (0.56-fold, P=0.19), F1 (0.45-fold, P=0.023), and F2 (0.35-fold, P=0.014) generations of WT mice, but not PPARα-null mice. Our data indicate that transgenerational repression by DEHP of ovarian Esr1 gene expression is mediated by PPARα-dependent pathways. Further studies are required to elucidate the mechanisms underlying crosstalk between PPARα and Esr1 signaling in reproductive processes.

SH3P2 is a negative regulator of cell motility whose function is inhibited by ribosomal S6 kinase-mediated phosphorylation.

Although the extracellular signal-regulated kinase (ERK) pathway functions downstream of Ras in induction of the cell motility response, the detailed molecular mechanism by which this pathway regulates cell motility has remained elusive. The application of a functional expression cloning strategy to discover proteins that regulate cell motility has resulted in the identification of an SH3 domain-containing protein, SH3P2. Overexpression of SH3P2 in HeLa S3 cells inhibited cell motility, whereas RNA interference-mediated depletion of SH3P2 enhanced motility in various tumor cell lines, suggesting that SH3P2 functions as a negative regulator of cell motility. The expression level of SH3P2 alone did not correlate well with the motility of tumor cells, however. SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility. The RSK inhibitor BI-D1870 suppressed SH3P2 phosphorylation and tumor cell motility as effectively as did the MEK inhibitor PD184352. Furthermore, expression of the unphosphorylatable SH3P2 mutant SH3P2(S202A) inhibited tumor cell motility, indicating that phosphorylation of SH3P2 at Ser(202) is a key determinant of such motility. These results suggest that SH3P2 is an essential molecule that functions downstream of the ERK pathway to modulate cell motility.

BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens.

A ligand-receptor pair, bone morphogenetic protein-7 (BMP7) and activin receptor IIB (actRIIB), was identified from a pool of DNA fragments recovered from MCF7 cells treated with 17beta-estradiol (E2) by chromatin immunoprecipitation with antiestrogen receptor-alphaantibody. The E2 responsiveness of both genes was confirmed in MCF cells and in the mouse uterus. Repeated treatment with E2 resulted in decreased expression of both actRIIB and BMP7 mRNA in the uteri of ovariectomized mice. A single oral administration of bisphenol A (BPA), an environmental estrogen, inhibited actRIIB and BMP7 expression and apoptosis in the luminal epithelium of the mouse uterus at diestrus (or early proestrus). This decrease, due to BPA administration, was restored by an estrogen receptor (ER) antagonist suggesting that it is mediated through ERs. These results suggest that E2 and BPA suppress estrogen-dependent apoptosis of epithelial cells of the endometrium through down-regulation of actRIIB and BMP7. Thus, we propose that BMP7 and actRIIB, a ligand-receptor pair, are involved in regulation of the apoptotic signaling pathway and might therefore be new biomarkers of the effects of environmental estrogens on the female reproductive tract.