Faculty Profiles - OTSUKA Fumio

Papers - OTSUKA Fumio

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Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-α in C2C12 cells

Yoshinori Matsumoto, Fumio Otsuka, Mariko Takano, Tomoyuki Mukai, Ryutaro Yamanaka, Masaya Takeda, Tomoko Miyoshi, Kenichi Inagaki, Ken-ei Sada, Hirofumi Makino

Molecular and Cellular Endocrinology 325 ( 1-2 ) 118 - 127 2010.8

Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling

Misuzu Yamashita, Fumio Otsuka, Tomoyuki Mukai, Ryutaro Yamanaka, Hiroyuki Otani, Yoshinori Matsumoto, Eri Nakamura, Mariko Takano, Ken-ei Sada, Hirofumi Makino

Regulatory Peptides 162 ( 1-3 ) 99 - 108 2010.6

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Ryutaro Yamanaka, Fumio Otsuka, Kazufumi Nakamura, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Yoshinori Matsumoto, Kengo F Kusano, Hiroshi Ito, Hirofumi Makino

Hypertension Research 33 ( 5 ) 435 - 445 2010.5

Effects of Bone Morphogenetic Protein (BMP) on Adrenocorticotropin Production by Pituitary Corticotrope Cells: Involvement of Up-Regulation of BMP Receptor Signaling by Somatostatin Analogs

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Ryutaro Yamanaka, Kenichi Inagaki, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Endocrinology 151 ( 3 ) 1129 - 1141 2010.3

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH2-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.

DOI： 10.1210/en.2009-1102

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骨軟骨と滑膜 BMPによる骨芽細胞分化に対するTNF-αおよびsteroidの作用機序の検討

松本佳則, 大塚文男, 向井知之, 高野真理子, 山中龍太郎, 山下美鈴, 塚本尚子, 佐田憲映, 槇野博史

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 54回・19回 526 - 526 2010.3

Multiple endocrine regulation by bone morphogenetic protein system.

Fumio Otsuka

Endocrine journal 57 ( 1 ) 3 - 14 2010.1

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

Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, 4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothesis that BMPs are a physiological luteinization inhibitor in growing ovarian follicles during the follicular phase of the ovarian cycle. The physiological importance of the BMP system for normal mammalian reproduction has been further recognized by the discovery of aberrant reproductive phenotypes of female sheep and humans having mutated genes encoding BMP-15. Physiological roles of BMPs in the pituitary, hypothalamus, adrenal and other tissues have also been discovered. Here we discuss recent advances in the understanding of autocrine/paracrine actions of BMPs in the systemic regulation of endocrine function.

DOI： 10.1507/endocrj.K09E-310

Inhibitory Effects of Simvastatin on Platelet-derived Growth Factor Signaling in Pulmonary Artery Smooth Muscle Cells From Patients With Idiopathic Pulmonary Arterial Hypertension

Tetsuya Ikeda, Kazufumi Nakamura, Satoshi Akagi, Kengo Fukushima Kusano, Hiromi Matsubara, Hideki Fujio, Aiko Ogawa, Aya Miura, Daiji Miura, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Hiroshi Date, Tohru Ohe, Hiroshi Ito

Journal of Cardiovascular Pharmacology 55 ( 1 ) 39 - 48 2010.1

Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells

Hiroyuki Otani, Fumio Otsuka, Masaya Takeda, Tomoyuki Mukai, Tomohiro Terasaka, Tomoko Miyoshi, Kenichi Inagaki, Jiro Suzuki, Toshio Ogura, Mark A Lawson, Hirofumi Makino

Journal of Endocrinology 203 ( 1 ) 87 - 97 2009.10

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

Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary–gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor α (ERα; ESR1 as listed in MGI Database), ERβ (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E₂) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E₂ activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH₂-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E₂ actions. Expression levels of Erα and Erβ were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E₂ effects on Gnrh suppression including reduction of E₂-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER–MAPK signaling. Considering that BMP6 and BMP7 increased the expression of α1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism.

DOI： 10.1677/joe-09-0065

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p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4

Kenichi Inagaki, Fumio Otsuka, Tomoko Miyoshi, Misuzu Yamashita, Mina Takahashi, Junko Goto, Jiro Suzuki, Hirofumi Makino

Endocrinology 150 ( 4 ) 1921 - 1930 2009.4

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Roles of the p38-MAPK pathway in steroidogenesis were investigated using coculture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective activin receptor-like kinase-4, -5, and -7 inhibitor, SB431542. SB431542 decreased FSH-induced estradiol but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. Bone morphogenetic protein (BMP)-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin (FSK)-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4, and activin increased FSH-induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced FSK-induced estradiol, BMP-2 and BMP-4 had no effects on FSK-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH-receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH-induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from the cAMP-protein kinase A pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH-induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, whereas the latter leads to reduction of progesterone synthesis.

DOI： 10.1210/en.2008-0851

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Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells

Junko Goto, Fumio Otsuka, Misuzu Yamashita, Jiro Suzuki, Hiroyuki Otani, Hiroko Takahashi, Tomoko Miyoshi, Yukari Mimura, Toshio Ogura, Hirofumi Makino

American Journal of Physiology-Endocrinology and Metabolism 296 ( 4 ) E904 - E916 2009.4

Publishing type：Research paper (scientific journal) Publisher：American Physiological Society

Here we investigated the effects of mineralocorticoid in the regulation of catecholamine biosynthesis using rat pheochromocytoma PC12 cells. Expression of mineralocorticoid receptor (MR) was confirmed in undifferentiated PC12 cells. Aldosterone stimulated dopamine production by PC12 cells without any increase in cAMP activity. Aldosterone-induced dopamine accumulation was enhanced in accordance with the increase in the rate-limiting enzyme tyrosine hydroxylase (TH). Blocking MR with eplerenone suppressed aldosterone-induced increases of TH mRNA and dopamine production. A glucocorticoid receptor (GR) antagonist, RU-486, attenuated dexamethasone- but not aldosterone-induced TH expression. Cycloheximide reduced both aldosterone- and dexamethasone-induced TH mRNA. A SAPK/JNK inhibitor, SP600125, suppressed aldosterone-induced TH mRNA expression; however, the aldosterone-induced TH expression was not affected by inhibition of ERK1/2, p38-MAPK, Rho-kinase, PI 3-kinase, and PKC. It was of note that cotreatment with eplerenone and SP600125 restored aldosterone-induced TH mRNA expression to basal levels. To investigate the involvement of bone morphogenetic protein (BMP) actions in aldosterone-induced catecholamine production, we examined the effects of BMP-4 and BMP-7, which are expressed in the adrenal medulla, on catecholamine biosynthesis. BMP-4 preferentially enhanced aldosterone-induced TH mRNA and dopamine production, although BMP-4 alone did not affect TH expression. The BMP-4 enhancement of aldosterone-induced TH expression was not observed in cells treated with eplerenone. BMP-4 did not affect MR expression of PC12 cells; however, it did enhance aldosterone-induced SAPK/JNK phosphorylation. Inhibition of SAPK/JNK or Rho suppressed BMP-4 enhancement of aldosterone-induced TH expression. Collectively, our findings demonstrate that aldosterone stimulates catecholamine biosynthesis in adrenomedullar cells via MR through genomic action and partly through nongenomic action by Rho-SAPK/JNK signaling, the latter of which is facilitated by BMP-4. A functional link between MR actions and endogenous BMP may be involved in the catecholamine production.

DOI： 10.1152/ajpendo.90840.2008

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骨粗鬆症破骨細胞活性化に対するBMP-2の影響とsimvastatinの作用機序の検討

山下美鈴, 大塚文男, 向井知之, 山中龍太郎, 矢野隆介, 山村昌弘, 槇野博史

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 53回・18回 283 - 283 2009.3

Adrenal ganglioneuroma accompanying catecholamine-producing adrenocortical cells

J. Goto, F. Otsuka, M. Omori, H. Makino

Journal of Endocrinological Investigation 32 ( 2 ) 192 - 192 2009.2

Effects of Growth Hormone Reduction in a Patient with Polycystic Ovary Syndrome Complicated with Acromegaly

Junko GOTO, Fumio OTSUKA, Kenichi INAGAKI, Naoko TSUKAMOTO, Jiro SUZUKI, Tomoko MIYOSHI, Toshio OGURA, Yasuhiko KAMADA, Hirofumi MAKINO

Endocrine Journal 56 ( 1 ) 157 - 160 2009

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Mina Takahashi, Fumio Otsuka, Tomoko Miyoshi, Hiroyuki Otani, Junko Goto, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino, Hiroyoshi Doihara

Journal of Endocrinology 199 ( 3 ) 445 - 455 2008.12

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

Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

DOI： 10.1677/joe-08-0226

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[Pulmonary arterial hypertension and BMP system abnormality].

Fumio Otsuka

Nihon rinsho. Japanese journal of clinical medicine 66 ( 11 ) 2083 - 90 2008.11

Language：Japanese

Genetic analysis has uncovered that familial and idiopathic pulmonary arterial hypertension (PAH) is linked to germline mutations in BMP type II receptor (BMPRII). PAH is characterized by enhanced remodeling of pulmonary arteries due to arterial smooth muscle cell proliferation. BMPRII mutations contribute to abnormal mitotic responses to BMP ligands in pulmonary artery smooth muscle cells. Unbalanced Smad signaling induced by BMP and TGFbeta is functionally involved in the pathogenesis of PAH. BMPRII mutations also increase the susceptibility of endothelial cell apoptosis. The combination of increased endothelial injury and impaired suppression of smooth muscle cell proliferation is critical for the cellular pathogenesis of PAH. However, the detailed molecular mechanism leading to severe vascular remodeling caused by BMPRII mutations has yet to be elucidated.

Other Link： http://search.jamas.or.jp/link/ui/2008376655

Aldosterone Breakthrough Caused by Chronic Blockage of Angiotensin II Type 1 Receptors in Human Adrenocortical Cells: Possible Involvement of Bone Morphogenetic Protein-6 Actions

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

Endocrinology 149 ( 6 ) 2816 - 2825 2008.6

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

DOI： 10.1210/en.2007-1476

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Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

Tomoko Miyoshi, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Junko Goto, Misuzu Yamashita, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Journal of Endocrinology 197 ( 1 ) 159 - 169 2008.4

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

Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0.1 μM) of OCT in combination with BRC (1–100 μM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 μM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

DOI： 10.1677/joe-07-0549

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TNF-αによる骨芽細胞分化の抑制に対するSimvastatin作用の検討

山下美鈴, 大塚文男, 向井知之, 相田哲史, 山村昌弘, 槇野博史

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 52回・17回 247 - 247 2008.4

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Misuzu Yamashita, Fumio Otsuka, Tomoyuki Mukai, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Junko Goto, Masahiro Yamamura, Hirofumi Makino

Journal of Endocrinology 196 ( 3 ) 601 - 613 2008.3

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

Recent studies have shown that the mevalonate pathway plays an important role in skeletal metabolism. Statins stimulate bone morphogenetic proteins-2 (BMP-2) production in osteoblasts, implicating a possible beneficial role for statins in promoting anabolic effects on bone. Here, we investigated the effects of a lipophilic simvastatin on osteoblast differentiation using mouse myoblast C2C12 cells, in the presence of tumor necrosis factor-α (TNF-α), an inflammatory cytokine that inhibits osteogenesis. The addition of TNF-α to C2C12 cells suppressed the BMP-2-induced expression of key osteoblastic markers including Runx2 and alkaline phosphatase (ALP) activity. Simvastatin had no independent effects on Runx2 and alkaline phosphatase activity; however, it reversed the suppressive effects of TNF-α. The ability of simvastatin to reverse TNF-α inhibition of BMP-induced Smad1,5,8 phosphorylation and Id-1 promoter activity suggests the involvement of Smad signaling pathway in simvastatin action. In addition, cDNA array analysis revealed that simvastatin increased expression levels of Smads in C2C12 cells exposed to TNF-α that also activated mitogen-activated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), P38, and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Simvastatin potently suppressed TNF-α-induced phosphorylation of ERK1/2 and SAPK/JNK by inhibiting TNF-α-induced membrane localization of Ras and RhoA. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) reversed the simvastatin effects on TNF-α-induced activation of Ras/Rho/MAPK pathways. FPP and GGPP also restored the simvastatin effects on TNF-α-induced suppression of Runx2 and ALP activity. In addition, simvastatin decreased the expression levels of TNF type-1 and -2 receptor mRNAs. Collectively, simvastatin supports BMP-induced osteoblast differentiation through antagonizing TNF-α-to-Ras/Rho/MAPK pathway and augmenting BMP-Smad signaling, suggesting a potential usage of statins to ameliorate inflammatory bone damage.

DOI： 10.1677/joe-07-0532

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Other Link： https://joe.bioscientifica.com/downloadpdf/journals/joe/196/3/601.xml

A Rare Tumor in the Adrenal Region: Neuron-specific Enolase (NSE)-Producing Leiomyosarcoma in an Elderly Hypertensive Patient

Junko GOTO, Fumio OTSUKA, Ryo KODERA, Tomoko MIYOSHI, Masaru KINOMURA, Hiroyuki OTANI, Yukari MIMURA, Toshio OGURA, Hiroyuki YANAI, Yasutomo NASU, Hirofumi MAKINO

Endocrine Journal 55 ( 1 ) 175 - 181 2008

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