研究者詳細 - 大塚　文男

論文 - 大塚　文男

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Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells

Masaya Takeda, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Jiro Suzuki, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Journal of Endocrinology 194 ( 1 ) 87 - 99 2007年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：Bioscientifica

Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lβ T2, which expresses activin/BMP receptors, transcription factor Smads, PPARα , and PPARγ . In Lβ T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lβ T2; whereas the PPARα agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)⁹-Luc activity. Both PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ , LHβ , and GnRHR. Activation of PPARα and PPARγ increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-β B mRNA in Lβ T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

DOI： 10.1677/joe-07-0138

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その他リンク： https://joe.bioscientifica.com/downloadpdf/journals/joe/194/1/1940087.xml

TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling

Tomoyuki Mukai, Fumio Otsuka, Hiroyuki Otani, Misuzu Yamashita, Koji Takasugi, Kenichi Inagaki, Masahiro Yamamura, Hirofumi Makino

Biochemical and Biophysical Research Communications 356 ( 4 ) 1004 - 1010 2007年5月

Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Tomoko Miyoshi, Jiro Suzuki, Tomoyuki Mukai, Toshio Ogura, Hirofumi Makino

American Journal of Physiology-Renal Physiology 292 ( 5 ) F1513 - F1525 2007年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Physiological Society

Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

DOI： 10.1152/ajprenal.00402.2006

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バセドウ病ともやもや病を合併し経過中に脳梗塞を発症した1型糖尿病の1例

更井啓, 四方賢一, 大森一慶, 佐藤千景, 西下伸吾, 和田淳, 鈴木二郎, 大塚文男, 槇野博史, 山本久美子, 佐々原渉

糖尿病 50 ( 5 ) 356 - 356 2007年5月

骨形成蛋白(BMP)により誘導される骨芽細胞分化に対する炎症性サイトカインTNF-αの抑制作用

大塚文男, 向井知之, 大谷寛之, 稲垣兼一, 三好智子, 後藤順子, 鈴木二郎, 三村由香里, 小倉俊郎, 槇野博史

日本内分泌学会雑誌 83 ( 1 ) 155 - 155 2007年4月

BMPによる骨芽細胞の分化に及ぼすTNF-αの作用メカニズムの検討

向井知之, 大塚文男, 山下美鈴, 高杉幸司, 相田哲史, 槇野博史, 山村昌弘

日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 51回・16回 365 - 365 2007年4月

Regulatory expression of bone morphogenetic protein-6 system in aldosterone production by human adrenocortical cells

Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Hiroyuki Otani, Masaya Takeda, Yoshihiro Kano, Tomoko Miyoshi, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino

Regulatory Peptides 138 ( 2-3 ) 133 - 140 2007年2月

Differential Regulation of Steroidogenesis by Bone Morphogenetic Proteins in Granulosa Cells: Involvement of Extracellularly Regulated Kinase Signaling and Oocyte Actions in Follicle-Stimulating Hormone-Induced Estrogen Production

Tomoko Miyoshi, Fumio Otsuka, Kenichi Inagaki, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Junko Goto, Toshio Ogura, Hirofumi Makino

Endocrinology 148 ( 1 ) 337 - 345 2007年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：The Endocrine Society

In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.

DOI： 10.1210/en.2006-0966

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Apparent mineralocorticoid excess manifested in an elderly patient with hypothyroidism. 査読国際誌

Inagaki K, Otsuka F, Otani H, Sato C, Miyoshi T, Ogura T, Makino H

American Journal of Hypertension 20 ( 1 ) 104 - 7 2007年1月

Primary Aldosteronism Caused by a Unilateral Adrenal Adenoma Accompanied by Autonomous Cortisol Secretion

Jiro SUZUKI, Fumio OTSUKA, Kenichi INAGAKI, Hiroyuki OTANI, Tomoko MIYOSHI, Tomohiro TERASAKA, Toshio OGURA, Masako OMORI, Yasutomo NASU, Hirofumi MAKINO

Hypertension Research 30 ( 4 ) 367 - 373 2007年

Gastric Diverticulum Simulating Left Adrenal Incidentaloma in a Hypertensive Patient

Ryo KODERA, Fumio OTSUKA, Kenichi INAGAKI, Tomoko MIYOSHI, Toshio OGURA, Yasushi TANIMOTO, Tetsuro SEI, Hirofumi MAKINO

Endocrine Journal 54 ( 6 ) 969 - 974 2007年

Mutual Regulation of Follicle-Stimulating Hormone Signaling and Bone Morphogenetic Protein System in Human Granulosa Cells1

Tomoko Miyoshi, Fumio Otsuka, Jiro Suzuki, Masaya Takeda, Kenichi Inagaki, Yoshihiro Kano, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Biology of Reproduction 74 ( 6 ) 1073 - 1082 2006年6月

Involvement of Bone Morphogenetic Protein-6 in Differential Regulation of Aldosterone Production by Angiotensin II and Potassium in Human Adrenocortical Cells

Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Yoshihiro Kano, Masaya Takeda, Tomoko Miyoshi, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Endocrinology 147 ( 6 ) 2681 - 2689 2006年6月

Manifestation of Rheumatoid Arthritis after Transsphenoidal Surgery in a Patient with Acromegaly

Tomoko MIYOSHI, Fumio OTSUKA, Tomoko KAWABATA, Kenichi INAGAKI, Tomoyuki MUKAI, Masanori KAWASHIMA, Toshio OGURA, Masahiro YAMAMURA, Tetsuro SEI, Hirofumi MAKINO

Endocrine Journal 53 ( 5 ) 621 - 625 2006年

Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis

Koji Takasugi, Masahiro Yamamura, Mitsuhiro Iwahashi, Fumio Otsuka, Jiro Yamana, Katsue Sunahori, Masanori Kawashima, Masao Yamada, Hirofumi Makino

Arthritis Research & Therapy 8 ( 4 ) R126 - R126 2006年

Regulatory Roles of Bone Morphogenetic Proteins and Glucocorticoids in Catecholamine Production by Rat Pheochromocytoma Cells

Yoshihiro Kano, Fumio Otsuka, Masaya Takeda, Jiro Suzuki, Kenichi Inagaki, Tomoko Miyoshi, Manabu Miyamoto, Hiroyuki Otani, Toshio Ogura, Hirofumi Makino

Endocrinology 146 ( 12 ) 5332 - 5340 2005年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：The Endocrine Society

We here report a new physiological system that governs catecholamine synthesis involving bone morphogenetic proteins (BMPs) and activin in the rat pheochromocytoma cell line, PC12. BMP type I receptors, including activin receptor-like kinase-2 (ALK-2) (also referred to as ActRIA) and ALK-3 (BMPRIA), both type II receptors, ActRII and BMPRII, as well as the ligands BMP-2, -4, and -7 and inhibin/activin subunits were expressed in PC12 cells. PC12 cells predominantly secrete dopamine, whereas noradrenaline and adrenaline production is negligible. BMP-2, -4, -6, and -7 and activin A each suppressed dopamine and cAMP synthesis in a dose-dependent fashion. The BMP ligands also decreased 3,4-dihydroxyphenylalanine decarboxylase mRNA expression, whereas activin suppressed tyrosine hydroxylase expression. BMPs induced both Smad1/5/8 phosphorylation and Tlx2-Luc activation, whereas activin stimulated 3TP-Luc activity and p38 MAPK phosphorylation. ERK signaling was not affected by BMPs or activin. Dexamethasone enhanced catecholamine synthesis, accompanying increases in tyrosine hydroxylase and 3,4-dihydroxyphenylalanine decarboxylase transcription without cAMP accumulation. In the presence of dexamethasone, BMPs and activin failed to reduce dopamine as well as cAMP production. In addition, dexamethasone modulated mitotic suppression of PC12 induced by BMPs in a ligand-dependent manner. Furthermore, intracellular BMP signaling was markedly suppressed by dexamethasone treatment and the expression of ALK-2, ALK-3, and BMPRII was significantly inhibited by dexamethasone. Collectively, the endogenous BMP/activin system plays a key role in the regulation of catecholamine production. Controlling activity of the BMP system may be critical for glucocorticoid-induced catecholamine synthesis by adrenomedullar cells.

DOI： 10.1210/en.2005-0474

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An Extra-adrenal Abdominal Pheochromocytoma Causing Ectopic ACTH Syndrome

F OTSUKA, T MIYOSHI, K MURAKAMI, K INAGAKI, M TAKEDA, K UJIKE, T OGURA, M OMORI, H DOIHARA, Y TANAKA

American Journal of Hypertension 18 ( 10 ) 1364 - 1368 2005年10月

Essential Role of the Oocyte in Estrogen Amplification of Follicle-Stimulating Hormone Signaling in Granulosa Cells

Fumio Otsuka, R. Kelly Moore, Xia Wang, Shweta Sharma, Tomoko Miyoshi, Shunichi Shimasaki

Endocrinology 146 ( 8 ) 3362 - 3367 2005年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：The Endocrine Society

Abstract

The establishment of dominant ovarian follicles that are capable of ovulating fertilizable oocytes is a fundamental determinant of female fertility. This process is governed by pituitary gonadotropins as well as local ovarian factors. Within the follicle, estrogen acts in an autocrine/paracrine manner to enhance FSH action in the granulosa cells. These effects include the augmentation of P450aromatase expression and estradiol production. This feed-forward effect of estrogen is believed to play a key role in follicle dominance. Here we found the essential role of the oocyte in this physiological process using primary cultures of rat granulosa cells. In the presence, but not absence, of oocytes, estrogen amplified FSH-stimulated increases in mRNA expression of P450aromatase, FSH receptor, LH receptor, and inhibin α-, βA-, and βB-subunits as well as cAMP production. Thus, oocytes mediate the estrogen enhancement of FSH action in the granulosa cells. In comparison with FSH, cotreatment with estrogen and oocytes failed to amplify the stimulatory effects of forskolin or 8-bromoadenosine-cAMP on granulosa cell responses including P450aromatase mRNA expression and cAMP production, indicating that estrogen/oocytes amplify FSH action at a site upstream of adenylate cyclase. These findings support the novel conclusion that communication between the oocyte and granulosa cells plays a crucial role in mediating estrogen action during FSH-dependent folliculogenesis.

DOI： 10.1210/en.2005-0349

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インスリン抵抗性と肥満を合併したバーター症候群の1例

村上和敏, 四方賢一, 和田淳, 大塚文男, 江口潤, 向井知之

糖尿病 48 ( 6 ) 464 - 464 2005年6月

Functional roles of the bone morphogenetic protein system in thyrotropin signaling in porcine thyroid cells

Jiro Suzuki, Fumio Otsuka, Masaya Takeda, Kenichi Inagaki, Tomoko Miyoshi, Yukari Mimura, Toshio Ogura, Hiroyoshi Doihara, Hirofumi Makino

Biochemical and Biophysical Research Communications 327 ( 4 ) 1124 - 1130 2005年2月

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