Faculty Profiles - OTSUKA Fumio

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys. Reviewed International journal

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

Hypertension research : official journal of the Japanese Society of Hypertension 35 ( 3 ) 312 - 7 2012.3

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Recent studies have shown that bone morphogenetic proteins (BMPs), particularly BMP-7, have an inhibitory role in the development of various renal diseases. We previously reported antagonistic effects of BMPs on renal mesangial cell proliferation induced by aldosterone (Aldo) in vitro. In the present study, we investigated in vivo roles of BMPs in Aldo-induced renal glomerular injury. BALB/c mice aged 6 weeks were treated with Aldo injection (5 mu g per day, intraperitoneally) and/or oral administration of high-salt (2%) water for 9 weeks. Systemic blood pressure, body weight, kidney weight and daily proteinuria were not significantly changed by Aldo and/or high-salt treatment. However, renal histological examination revealed increases in glomerular cellularity and glomerular diameter in the groups treated with Aldo injection and high-salt administration. Immunohistochemistry demonstrated expression of BMP-4 and -7 in the glomerular mesangial region. Aldo causes renal glomerular damage by stimulating mesangial cell proliferation and increasing extracellular matrix via the mineralocorticoid receptor (MR). MR messenger RNA (mRNA) expression in the renal cortex was transiently increased by 3-week treatment with Aldo and high-salt intake, but was decreased by 9-week treatment. Furthermore, the expression levels of BMP-4 and -7 mRNA were enhanced in the renal cortex treated with Aldo and high-salt administration. These findings suggest that the renal BMP system is activated by Aldo under the condition of high-salt exposure, which may have a key role in antagonizing glomerular damage in vivo. Hypertension Research (2012) 35, 312-317; doi:10.1038/hr.2011.186; published online 10 November 2011

DOI： 10.1038/hr.2011.186

BMP action in the pituitary: its possible role in modulating somatostatin sensitivity in pituitary tumor cells. Reviewed International journal

Fumio Otsuka, Naoko Tsukamoto, Tomoko Miyoshi, Yasumasa Iwasaki, Hirofumi Makino

Molecular and cellular endocrinology 349 ( 2 ) 105 - 10 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The existence of a functional bone morphogenetic protein (BMP) system in the pituitary has been recognized. Recent studies have provided evidence that BMPs elicit differential actions in the regulation of prolactin (PRL) and adrenocorticotropin (ACTH) release in lactotropinoma and corticotropinoma cells, respectively. BMPs play a key role in the modulation of somatostatin receptor (SSTR) sensitivity of lactosomatotrope cells in an autocrine/paracrine manner. In addition, SSTR action enhances BMP responsiveness in corticotrope cells. The functional link between BMP receptor signaling and SSTR actions may be crucial for individual tolerance to somatostatin analogs for controlling PRL and ACTH production. Adjustment of the endogenous SSTR sensitivity may be an effective strategy to inhibit the growth activity and hormonal productivity of intractable pituitary tumors.

DOI： 10.1016/j.mce.2011.10.017

Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells. Reviewed International journal

Masaya Takeda, Fumio Otsuka, Hiroaki Takahashi, Kenichi Inagaki, Tomoko Miyoshi, Naoko Tsukamoto, Hirofumi Makino, Mark A Lawson

Molecular and cellular endocrinology 348 ( 1 ) 147 - 54 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

It is known that bone morphogenetic proteins (BMPs) regulate gonadotropin transcription and production by pituitary gonadotrope cells. However, the role of BMPs in gonadotropin-releasing hormone (GnRH)-induced FSH production remains uncertain. Here, we describe a functional link between BMP6 and BMP-7 signals and FSH transcriptional activity induced by GnRH using mouse gonadotrope L beta T2 cells. In L beta T2 cells, BMP-6 and BMP-7 increased mouse FSH beta-promoter activity in a concentration-dependent manner. The induction by BMP-6 and BMP-7 was inhibited by treatment with extracellular domains of ActRII but not BMPRII. These findings suggest that the type II receptor ActRII participates in BMP-induced FSH beta transcription regulation. Notably, BMP-6, but not BMP-7, enhanced GnRH-induced FSH beta-promoter activity in L beta T2 cells. Since GnRH stimulated MAPK phosphorylation in L beta T2 cells, a functional link between MAPK and FSH beta transcription was examined. Inhibition of the ERK pathway, but not that of p38 or SAPK/JNK signaling, suppressed GnRH-induced FSH beta transcription, suggesting that ERK is functionally involved in GnRH-induced FSH beta transcription. Co-treatment with BMP-7, but not with BMP-6, suppressed GnRH-induced MAPK phosphorylation in L beta T2 cells. Thus,, the difference between BMP-6 and BMP-7 in enhancing GnRH-induced FSH beta transcription may be due to the differential effects of BMP ligands on GnRH-induced ERK signaling. On the other hand, GnRH reduced Smad1/5/8 phosphorylation but increased Smad6/7 expression. These findings imply the presence of a functional link between GnRH action, MAPK signaling and the BMP system in pituitary gonadotropes for fine-tuning of FSH gene expression. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2011.08.001

Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-α. Reviewed International journal

Mariko Takano, Fumio Otsuka, Yoshinori Matsumoto, Kenichi Inagaki, Masaya Takeda, Eri Nakamura, Naoko Tsukamoto, Tomoko Miyoshi, Ken-ei Sada, Hirofumi Makino

Molecular and cellular endocrinology 348 ( 1 ) 224 - 32 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Recent studies have suggested possible adverse effects of thiazolidinediones on bone metabolism. However, the detailed mechanism by which the activity of PPAR affects bone formation has not been elucidated. Impaired osteoblastic function due to cytokines is critical for the progression of inflammatory bone diseases. In the present study, we investigated the cellular mechanism by which PPAR actions interact with osteoblast differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. BMP-2 and -4 potently induced the expression of various bone differentiation markers including Runx2, osteocalcin, type-1 collagen and alkaline phosphatase (ALP) in C2C12 cells. When administered in combination with a PPAR alpha agonist (fenofibric acid) but not with a PPAR gamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR alpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPAR alpha and PPAR gamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NF kappa B, I kappa B and Stat pathways was inhibited in the presence of PPAR alpha and PPAR gamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK. Stat and NF kappa B pathways reversed the TNF-alpha suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-alpha-induced suppression of osteoblast differentiation. It was further discovered that the PPAR alpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR gamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR alpha and PPAR gamma in the process of osteoblast differentiation. Thus, PPAR alpha actions promote BMP-induced osteoblast differentiation, while both activities of PPAR alpha and PPAR gamma suppress TNF-alpha actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-alpha receptor signaling that is crucial for bone metabolism. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2011.08.027

Mutual regulation of growth hormone and bone morphogenetic protein system in steroidogenesis by rat granulosa cells. Reviewed International journal

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

Endocrinology 153 ( 1 ) 469 - 80 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Yoshinori Matsumoto, Ken-ei Sada, Mariko Takano, Noriko Toyota, Ryutaro Yamanaka, Koichi Sugiyama, Hiroshi Wakabayashi, Tomoko Kawabata, Fumio Otsuka, Hirofumi Makino

Acta Medica Okayama 65 ( 5 ) 329 - 334 2011.10

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

Fumio Otsuka, Kenichi Inagaki

Reproductive medicine and biology 10 ( 3 ) 131 - 142 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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 2011.9

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 2011.8

Rhabdomyosarcoma discovered in the adrenal region of an elderly hypertensive patient

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

Hypertension Research 34 ( 6 ) 784 - 786 2011.6

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 2011.5

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 2011.3

Integral role of GDF-9 and BMP-15 in ovarian function. International journal

Fumio Otsuka, Kirsten J McTavish, Shunichi Shimasaki

Molecular reproduction and development 78 ( 1 ) 9 - 21 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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 2011.1

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

Internal Medicine 50 ( 21 ) 2669 - 2673 2011

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 2010.11

Publishing type：Research paper (scientific journal) Publisher：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 2010.9

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 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：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