研究者詳細 - 大塚　文男

Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells. 査読国際誌

Takeda M, Otsuka F, Takahashi H, Inagaki K, Miyoshi T, Tsukamoto N, Makino H, Lawson MA

Mol Cell Endocrinol 348 ( 1 ) 147 - 54 2012年1月

Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-α. 査読国際誌

Takano M, Otsuka F, Matsumoto Y, Inagaki K, Takeda M, Nakamura E, Tsukamoto N, Miyoshi T, Sada KE, Makino H

Molecular and cellular endocrinology 348 ( 1 ) 224 - 32 2012年1月

Mutual regulation of growth hormone and bone morphogenetic protein system in steroidogenesis by rat granulosa cells. 査読国際誌

Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Tomoko Miyoshi, Yoshinori Matsumoto, Kanako Ogura, Naoko Tsukamoto, Masaya Takeda, Hirofumi Makino

Endocrinology 153 ( 1 ) 469 - 80 2012年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ENDOCRINE SOC

GH induces preantral follicle growth and differentiation with oocyte maturation. However, the effects of GH on ovarian steroidogenesis and the mechanisms underlying its effects have yet to be elucidated. In this study, we investigated the actions of GH on steroidogenesis by rat granulosa cells isolated from early antral follicles by focusing on the ovarian bone morphogenetic protein (BMP) system. We found that GH suppressed FSH-induced estradiol production with reduction in aromatase expression and, in contrast, GH increased FSH-induced progesterone level with induction of steroidogenic acute regulatory protein, side chain cleavage cytochrome P450, and 3 beta-hydroxysteroid dehydrogenase. The effects of GH on steroidogenesis by granulosa cells were enhanced in the presence of the BMP antagonist noggin. Coculture of GH with oocytes did not alter GH regulation of steroidogenesis. Steroid production induced by cAMP donors was not affected by GH treatment and the GH effects on FSH-induced steroid production were not accompanied by changes in cAMP synthesis, suggesting that GH actions were not directly mediated by the cAMP-protein kinase A pathway. GH exerted synergistic effects on MAPK activation elicited by FSH, which regulated FSH-induced steroidogenesis. In addition, GH-induced signal transducer and activator of transcription phosphorylation was involved in the induction of IGF-I expression. GH increased IGF-I, IGF-I receptor, and FSH receptor expression in granulosa cells, and inhibition of IGF-I signaling restored GH stimulation of FSH-induced progesterone production, suggesting that endogenous IGF-I is functionally involved in GH effects on progesterone induction. BMP inhibited IGF-I effects that increased FSH-induced estradiol production with suppression of expression of the GH/IGF-I system, whereas GH/IGF-I actions impaired BMP-Sma and Mad related protein 1/5/8 signaling through down-regulation of the expression of BMP receptors. Thus, GH acts to modulate estrogen and progesterone production differentially through endogenous IGF-I activity in granulosa cells, in which GH-IGF-I interaction leads to antagonization of BMP actions including suppression of FSH-induced progesterone production. Mutual balance between GH/IGF-I and BMP signal intensities may be a key for regulating gonadotropin-induced steroidogenesis in growing follicles. (Endocrinology 153: 469-480, 2012)

DOI： 10.1210/en.2011-1646

Risk Factors for Infection in Patients with Remitted Rheumatic Diseases Treated with Glucocorticoids

Acta Medica Okayama 65 ( 5 ) 329 - 334 2011年10月

記述言語：英語出版者・発行元：Okayama University Medical School

It is well known that infection is one of the major causes of morbidity and mortality in rheumatic disease patients treated with high-dose glucocorticoids, especially in the early phase after achievement of disease remission. The aim of this study was to identify the risk factors for infection, with a focus on the dose of glucocorticoids administered, following the achievement of disease remission in rheumatic diseases patients. We retrospectively analyzed the medical records of rheumatic disease patients who had been treated with glucocorticoids. The primary endpoint was the incidence rate of infection during a period from 1 to 2 months after the commencement of treatment. From April 2006 to March 2010, 19 of 92 patients suffered from infection during the observation period. Age≧65 yrs, presence of interstitial pneumonia, diagnosis of systemic vasculitis and serum creatinine level≧2.0mg/dl were found to be univariate predictors for infection. However, only the presence of interstitial pneumonia was an independent risk factor for infection (HR＝4.50, 95%CI＝1.65 to 14.44) by the Cox proportional hazard model. Even after achievement of clinical remission, careful observation is needed for patients with interstitial pneumonia, more so than for those receiving high-dose glucocorticoids.

DOI： 10.18926/AMO/47015

CiNii Article

CiNii Books

Rhabdomyosarcoma discovered in the adrenal region of an elderly hypertensive patient

その他リンク： http://search.jamas.or.jp/link/ui/2012272289

Unique bioactivities of bone morphogenetic proteins in regulation of reproductive endocrine functions.

Fumio Otsuka, Kenichi Inagaki

Reproductive medicine and biology 10 ( 3 ) 131 - 142 2011年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：John Wiley and Sons Ltd

Remarkable progress has been made in understanding the mechanism by which growth factors and oocytes can regulate the development and function of granulosa cells. Insufficiency of two oocyte-specific growth factors, growth differentiation factor-9 and bone morphogenetic protein (BMP)-15, cause female infertility. Expression of mRNA and/or protein for the BMP system components, including ligands, receptors and intracellular signal transduction factors, was demonstrated in cell components of growing preantral follicles, and biofunctional experiments have further revealed many important roles of the BMP system in regulation of reproductive function. In this review, recent advances in studies on biological actions of BMPs in ovarian folliculogenesis and in related endocrine tissues are discussed. © 2011 Japan Society for Reproductive Medicine.

DOI： 10.1007/s12522-011-0082-9

Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Tomohiro Terasaka, Masaya Takeda, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Molecular and Cellular Endocrinology 344 ( 1-2 ) 41 - 50 2011年9月

Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation

Hiroko Masuda, Fumio Otsuka, Yoshinori Matsumoto, Mariko Takano, Tomoko Miyoshi, Kenichi Inagaki, Tadahiko Shien, Naruto Taira, Hirofumi Makino, Hiroyoshi Doihara

Molecular and Cellular Endocrinology 343 ( 1-2 ) 7 - 17 2011年8月

Akihiro Katayama, Fumio Otsuka, Masaya Takeda, Tomoko Miyoshi, Eri Nakamura, Kenichi Inagaki, Takehiro Tanaka, Shinya Uehara, Hirofumi Makino

Hypertension Research 34 ( 6 ) 784 - 786 2011年6月

Unexpected occurrence of adrenal Cushing’s syndrome in a patient with systemic lupus erythematosus

Akihiro Katayama, Fumio Otsuka, Katsuyuki Tanabe, Naoko Tsukamoto, Ryutaro Yamanaka, Yoshinori Matsumoto, Yasutomo Nasu, Hirofumi Makino

Hypertension Research 34 ( 5 ) 662 - 663 2011年5月

Effects of eplerenone on nephrotic syndrome in a patient with renovascular hypertension

Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Katsuyuki Tanabe, Naoko Tsukamoto, Tomoko Miyoshi, Eri Nakamura, Toshio Ogura, Isao Kumagai, Hirofumi Makino

Hypertension Research 34 ( 3 ) 404 - 406 2011年3月

Integral role of GDF-9 and BMP-15 in ovarian function. 国際誌

Fumio Otsuka, Kirsten J McTavish, Shunichi Shimasaki

Molecular reproduction and development 78 ( 1 ) 9 - 21 2011年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-LISS

The oocyte plays an important role in regulating and promoting follicle growth, and thereby its own development, by the production of oocyte growth factors that predominantly act on supporting granulosa cells via paracrine signaling. Genetic studies in mice demonstrated critical roles of two key oocyte-derived growth factors belonging to the transforming growth factor-beta (TGF-beta) superfamily, growth and differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15), in ovarian function. The identification of Bnip15 and Gdf9 gene mutations as the causal mechanism underlying the highly prolific or infertile nature of several sheep strains in a dosage-sensitive manner also highlighted the crucial role these two genes play in ovarian function. Similarly, large numbers of mutations in the GDF9 and BMP15 genes have been identified in women with premature ovarian failure and in mothers of dizygotic: twins. The purpose of this article is to review the genetic studies of GDF-9 and BMP-15 mutations identified in women and sheep, as well as describing the various knockout and overexpressing mouse models, and to summarize the molecular and biological functions that underlie the crucial role of these two oocyte factors in female fertility. Mol. Reprod. Dev.78: 9-21, 2011. (c) 2010 Wiley-Liss, Inc.

DOI： 10.1002/mrd.21265

Systemic Lupus Erythematosus Complicated with Acute Myocardial Infarction and Ischemic Colitis

Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Molecular and Cellular Endocrinology 332 ( 1-2 ) 163 - 169 2011年1月

Yoshinori Matsumoto, Hiroshi Wakabayashi, Fumio Otsuka, Kentaro Inoue, Mariko Takano, Ken-ei Sada, Hirofumi Makino

Internal Medicine 50 ( 21 ) 2669 - 2673 2011年

A Novel Antagonistic Effect of the Bone Morphogenetic Protein System on Prolactin Actions in Regulating Steroidogenesis by Granulosa Cells

Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Tomoko Miyoshi, Ryutaro Yamanaka, Naoko Tsukamoto, Jiro Suzuki, Toshio Ogura, Hirofumi Makino

Endocrinology 151 ( 11 ) 5506 - 5518 2010年11月

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

To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3β-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin- and N6,O2-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL.

DOI： 10.1210/en.2010-0265

ステロイドによる骨芽細胞分化および炎症性骨分化抑制への影響

松本佳則, 大塚文男, 高野真理子, 向井知之, 武田昌也, 三好智子, 稲垣兼一, 槇野博史

日本内分泌学会雑誌 86 ( 2 ) 408 - 408 2010年9月

Roles of bone morphogenetic protein-6 in aldosterone regulation by adrenocortical cells.

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Jiro Suzuki, Hirofumi Makino

Acta medica Okayama 64 ( 4 ) 213 - 8 2010年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Aldosterone production occurs in the adrenal cortex, and is regulated primarily by angiotensin II (Ang II), potassium and adrenocorticotropin (ACTH). In the presence of the aldosterone stimulators, steroidogenesis is further governed by local autocrine and/or paracrine factors in the adrenal cortex. We reported the presence of functional bone morphogenetic protein (BMP) system in the adrenal cortex and also demonstrated that BMP-6 increases Ang II-induced aldosterone production, which could be involved in the "aldosterone breakthrough" phenomenon. Aldosterone breakthrough is the phenomenon by which circulating aldosterone concentrations increase above pre-treatment levels after longterm therapy with ACE inhibitors or Ang II type 1 receptor antagonists (ARB). This phenomenon may lead to important clinical consequences since increased aldosterone in a high-salt state facilitates cardiovascular and renal damage in hypertensive patients. We found that long-term ARB treatment reverses the reduction of aldosterone synthesis by adrenocortical cells, thereby causing "cellular aldosterone breakthrough". The availability of BMP-6 in the adrenal cortex may be at least partly involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

DOI： 10.18926/AMO/40128