Selective estrogen receptor modulators, acting as agonists of estrogen receptor α in osteoblasts, reduce the TGF-β-induced synthesis of macrophage colony-stimulating factor via inhibition of JNK signaling pathway.

IF 1.3 4区 医学 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Tomoyuki Hioki, Rie Matsusima-Nishiwaki, Haruhiko Tokuda, Osamu Kozawa
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引用次数: 1

Abstract

Selective estrogen receptor modulator (SERM) binds to estrogen receptors (ERs) and acts as both an agonist or an antagonist, depending on the target tissue. Raloxifene and bazedoxifene as SERMs are currently used hormone replacement medicines for postmenopausal osteoporosis. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts promotes osteoclastogenesis. We have previously demonstrated that transforming growth factor (TGF)-β induces the synthesis of M-CSF via SMAD2/3, p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and c-Jun N-terminal kinase (JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether SERM affects the M-CSF synthesis by TGF-β in MC3T3-E1 cells. Raloxifene and bazedoxifene significantly suppressed the synthesis of M-CSF. PPT, an ERα agonist, but not ERB041, an ERβ agonist, inhibited the release of M-CSF. MPP, an ERα antagonist, reversed the suppression by raloxifene of the M-CSF release. Raloxifene attenuated the TGF-β-induced phosphorylation of JNK but not SMAD3, p42 MAPK and p38 MAPK. Bazedoxifene and PPT also inhibited the phosphorylation of JNK. Furthermore, MPP, an ERα antagonist, reversed the suppression by both raloxifene and bazedoxifene of the phosphorylation of JNK. Our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-β-induced synthesis of M-CSF through ERα-mediated inhibition of JNK pathway in osteoblasts.

选择性雌激素受体调节剂作为成骨细胞雌激素受体α的激动剂,通过抑制JNK信号通路,减少TGF-β诱导巨噬细胞集落刺激因子的合成。
选择性雌激素受体调节剂(SERM)结合雌激素受体(er),并根据靶组织作为激动剂或拮抗剂。雷洛昔芬和巴兹多昔芬作为serm是目前用于绝经后骨质疏松症的激素替代药物。成骨细胞分泌巨噬细胞集落刺激因子(M-CSF)促进破骨细胞的发生。我们之前已经证明,在成骨细胞样MC3T3-E1细胞中,转化生长因子(TGF)-β通过SMAD2/3、p38丝裂原活化蛋白激酶(MAPK)、p44/p42 MAPK和c-Jun n末端激酶(JNK)诱导M-CSF的合成。在本研究中,我们研究了SERM是否影响TGF-β在MC3T3-E1细胞中合成M-CSF。雷洛昔芬和巴泽多昔芬明显抑制M-CSF的合成。ERα激动剂PPT能抑制M-CSF的释放,ERβ激动剂er041则不能。MPP,一种ERα拮抗剂,逆转了雷洛昔芬对M-CSF释放的抑制。雷洛昔芬能减弱TGF-β诱导的JNK磷酸化,但不能减弱SMAD3、p42 MAPK和p38 MAPK的磷酸化。巴泽多昔芬和PPT均能抑制JNK的磷酸化。此外,ERα拮抗剂MPP逆转了雷洛昔芬和巴泽多西芬对JNK磷酸化的抑制作用。我们的研究结果强烈表明,雷洛昔芬和巴泽多昔芬(SERMs)通过er α介导的JNK通路抑制成骨细胞中TGF-β诱导的M-CSF合成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomedical Research-tokyo
Biomedical Research-tokyo 医学-医学:研究与实验
CiteScore
2.40
自引率
0.00%
发文量
19
审稿时长
>12 weeks
期刊介绍: Biomedical Research is peer-reviewed International Research Journal . It was first launched in 1990 as a biannual English Journal and later became triannual. From 2008 it is published in Jan-Apr/ May-Aug/ Sep-Dec..
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