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Carboranes are a class of carbon-containing polyhedral boron-cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors. Estrogen deficiency results in marked bone loss due to increased osteoclastic bone resorption in females, but estrogen replacement therapy is not generally used for postmenopausal osteoporosis due to the risk of uterine cancer. We synthesized a novel carborane compound BE360 to clarify its anti-osteoporosis activity. BE360 showed a high binding affinity to estrogen receptors (ER), ERalpha and ERbeta. In ovariectomized (OVX) mice, femoral bone volume was markedly reduced and BE360 dose-dependently restored bone loss in OVX mice. However, BE360 did not exhibit any estrogenic activity in the uterus. BE360 also restored bone loss in orchidectomized mice without androgenic action in the sex organs. Therefore, BE360 is a novel selective estrogen receptor modulator (SERM) that may offer a new therapy option for osteoporosis.

Naringin is a flavonoid commonly found in citrus fruits. Previous studies have supported a positive association between fruit consumption and health including bone quality. To clarify the role of naringin in bone turnover, we examined the effect of naringin on bone mass in mice, and on osteoclast formation induced by bone-resorbing cytokine. When mice were orally administered naringin for 2 weeks, femoral bone mineral density (BMD) was clearly elevated compared with control mice. BMD in distal and middle portion was significantly enhanced, but proximal BMD was not changed by naringin administration. In soft-X-ray analysis, a marked accumulation of cancellous bone could be detected in distal femoral metasphysis in mice treated with naringin. In cocultures of bone marrow cells and osteoblasts, naringin dose-dependently suppressed the number of osteoclasts formed by treatment with interleukin-1 (IL-1). The size of osteoclasts formed in the presence of naringin was smaller than that induced by IL-1. Naringin enhances bone mass possibly by suppression of osteoclast formation in mice, suggesting the role of the citrus flavonoid on bone health and to prevent bone diseases such as osteoporosis.

Estrogen deficiency caused by ovariectomy (OVX) induces bone loss and increased B-lymphopoiesis in bone marrow. In OVX mice, the production of prostaglandin E (PGE) and the expression of receptor activator of nuclear factor-κB ligand (RANKL) were elevated in osteoblasts, and the cell adhesion of B cells induced RANKL expression in osteoblasts. However, the roles of PGE in RANKL expression and bone resorption are not clear. To examine the relationship between B-lymphopoiesis and PGE production by osteoblasts, B cells were purified from bone marrow, fixed, and co-cultured with mouse osteoblasts. Most of the fixed B cells adhered to cell surface of osteoblasts, and the cell-cell interaction markedly elevated the expression of cyclooxygenase (COX)-2 and membrane-bound PGE synthase (mPGES)-1 mRNAs, and PGE2 production in osteoblasts. Adding B cells also induced the expression of RANKL mRNA in osteoblasts, and the RANKL expression was suppressed by indomethacin, COX-2 inhibitor (NS398) and selective antagonist for PGE receptor EP4, suggesting that PGE production and EP4 signals are involved in RANKL-dependent bone resorption induced by cell-cell contact between B cells and osteoblasts. Therefore, the increased B-lymphopoiesis and PGE production by osteoblasts may contribute to the pathogenesis of osteoporosis due to estrogen deficiency.

The current collapse of normally-off mode AlGaN/GaN/AlGaN double heterojunction field effect transistors was investigated in comparison with the normal AlGaN/GaN heterojunction filed effect transistors.

Novel vitamin D analogs, 1alpha, 25-dihydroxyvitamin D(3)-26, 23-lactam (DLAMs) with a lactam moiety in the side chain, were synthesized and examined for their function in bone. In computer docking simulation, DLAM-1P binds to vitamin D receptor (VDR), and its lactam moiety may interfere with VDR helix-12 folding. In co-cultures of mouse bone marrow cells and osteoblasts, (23S,25S)-DLAM-1P dose-dependently suppressed osteoclast differentiation induced by 1alpha, 25-dihydroxyvitamin D(3) [1alpha, 25(OH)(2)D(3)]. Its stereoisomer (23R,25R)-DLAM-1P did not affect the osteoclast differentiation. In osteoblasts, (23S,25S)-DLAM-1P suppressed 1alpha, 25(OH)(2)D(3)-induced mRNA expression of the receptor activator of NF-kappaB ligand (RANKL). In an organ culture using mouse calvaria, bone-resorbing activity induced by 1alpha, 25(OH)(2)D(3) was clearly suppressed by (23S,25S)-DLAM-1P. The other analog, (23S,25S)-DLAM-2P, showed a similar activity to (23S,25S)-DLAM-1P. Therefore, DLAMs act on osteoblasts as an antagonist of 1alpha, 25(OH)(2)D(3) to suppress RANKL-dependent osteoclast formation, suggesting them as a novel candidate for the treatment of pathological bone loss.

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3], the active form of vitamin D3, is known to exhibit an anti-tumor properties and markedly suppresses the growth of various human cancer cells. We synthesized novel vitamin D analogs, 1α,25dihydroxyvitamin D3-26,23-lactam (DLAMs), having a lactam moiety in the side chain, and examined the effects on cell growth of human prostate cancer cells LNCaP. 1α,25(OH)2D3 significantly suppressed both the number of cells and cell viability. The mRNA expression of p21, well-known as a tumor suppressive gene, was clearly induced by treatment with 1α,25(OH)2D3 in LNCaP cells. The effects of 1α,25(OH)2D3 on the growth suppression of LNCaP cells was attenuated by the simultaneous addition of (23S,25S)-DLAM-1P. In a computer docking simulation, (23S,25S)-DLAM-1P bound to vitamin D receptor (VDR), and its lactam moiety may interfere VDR helix-12 folding. Its stereoisomer (23R,25R)-DLAM-1P did not influence cell growth regulated by 1α,25(OH)2D3. The expression of p21 mRNA induced by 1α,25(OH)2D3 was suppressed by (23S,25S)-DLAM-1P but not by (23R,25R)-DLAM1P in LNCaP cells. In the absence of 1α,25(OH)2D3, neither (23S,25S)-DLAM-1P nor (23R,25R)-DLAM1P regulated the cell growth of LNCaP cells. Thus, (23S,25S)-DLAM-1P interferes with the VDR signal and acts as a vitamin D3 antagonist in cancer cells.

Nearly normally-off operation of the GaN-based heterojunction field effect transistors was obtained using AlGaN/GaN/AlGaN double heterojunction channel. The aluminum compositions of the AlGaN heterobarriers are designed so as to deplete the electron carrier in the AlGaN/GaN/AlGaN channel, which gives the threshold gate voltage of about 0 V. The maximum drain current density was over 170 mA/mm. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We report the fabrication of AlGaN/GaN high electron mobility transistors (HEMT) with high-k /SiN and high-k /SiO2/SiN gate structures. HfO2, ZrO2, TiO2 and Ta2O5 were used as high-k materials. Both high-k /SiN and high-k /SiO2/SiN metal-insulator-semiconductor (MIS) HEMTs showed good operating characteristics. However, in the case of high-k /SiN MIS-HEMT, the off-state drain current was large. On the other hand, in the case of the high-k /SiO2/SiN MIS-HEMT, the off state current was significantly reduced due to the presence of the SiO2 layer, and the breakdown voltage characteristics were improved. The breakdown voltages of HfO2/SiO2/SiN MIS-HEMT and ZrO2/SiO2/SiN at gate-drain distance Lgd = 28 μm were 1.8 kV and 1.7 kV, respectively. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We investigated the gate-length dependence of room-temperature DC operation in submicron-gate AlGaN/GaN high-electron-mobility transistors (HEMTs). The threshold voltage was reduced by the short-channel effect, which is only dependent on the aspect ratio of the gate length to the barrier-layer thickness. On the other hand, the transconductance was restricted by the source resistance, and was dependent on not only the gate length LG but also the source?gate length LSG. The transconductance was increased by reducing LSG rather than LG in the submicron-gate HEMTs.

Vanilloid receptor-1 (VR1) has been reported to exhibit multiple functions which can transduce painsensitive signals in nerve systems. A VR1 ligand, capsaicin ,h as been reported to show activities against inflammation an dc ancer growth, however, its role in bone metabolism is still unknown. Here, we examined the effect of capsaici no n cytokine-induced inflammatory bone resorption. Capsaicin suppressed interleukin-1-induced bone resorption in a mouse calvarial organex vivo culture in a dose-dependent manner. An assay using cocultures ofosteoblastsand bone marrow cells clearly showed the inhibition of osteoclast formation by treatment with capsaicin. Receptor activator of NF-κB ligand (RANKL), the sole inducer of osteoclast formation, is known to be produced by osteoblasts. In th ec ocultures o fb one marrow cells and osteoblasts, the expression of RANKL was suppressed by capsaicin. VR1 showed expression predominantly in osteoblasts, suggesting that capsaicin directly modulates osteoclast differentiation through the suppression of RANKL expression. VR1 ligands like capsaicin have the potential for use as clinical drugs targeting some bone diseases involving cytokine-induced bone resorption.

Prostaglandin E2 (PGE2) is mainly produced by osteoblasts in bone tissue, and acts as a potent stimulator of bone resorption. In osteoblasts, PGE2 production was greatly stimulated by lipopolysaccharide (LPS) following the expression of cyclooxygenase (COX)-2 and membrane-bound PGE synthase (mPGES)-1 mRNA. In the coculture of mouse bone marrow cells and osteoblasts, LPS induced PGE production and osteoclast formation, and EP4 antagonist completely suppressed osteoclast formation, indicating that the PGE2-mediated EP4 signal is essential for LPS-induced osteoclast formation. Inflammatory bone diseases including periodontitis are known to be accompanied by bone loss with increased osteoclastogenesis. To examine the role of EP4-mediated PGE2 action in periodontitis, we examined the effects of EP4 antagonist on LPS-induced bone resorption using mouse alveolar bone. In an organ culture of alveolar bone, LPS-induced bone resorbing activity and EP4 antagonist suppressed this LPS-induced bone resorption. In an experimental model of periodontitis, LPS was injected into the lower gingiva, and the bone mineral density of alveolar bone was measured. LPS-induced the loss of alveolar bone, which was recovered by the treatment with EP4 antagonist in vivo. Therefore, EP4 antagonist is a possible candidate for the therapy of inflammatory bone disease including periodontitis.

Soy isoflavones, genistein, daidzein and its metabolite equol, as well as β-carotene have been reported to be effective for maintaining bone health. However, it remains to be elucidated whether combining soy isoflavones with β-carotene is beneficial to bone formation. This study investigated the combined effect of soy isoflavones and β-carotene on the differentiation of MC3T3-E1 preosteoblastic cells. Daidzein and genistein alone did not affect cell growth but increased alkaline phosphatase (ALP) activity. Beta-carotene alone inhibited cell growth and markedly enhanced ALP activity. Soy isoflavones combined with β-carotene resulted in higher ALP activity than treatment with isoflavones or β-carotene alone. We observed significant main effects of β-carotene on the enhanced expression of Runx2, ALP, and ostepontin mRNA, whereas there was a significant main effect of soy isoflavones on the expression of osterix mRNA. To investigate how β-carotene affected osteoblast differentiation, MC3T3-E1 cells were treated with retinoic acid receptor (RAR) pan-antagonist combined with β-carotene. Osteopontin and ALP mRNA expression levels, which were increased following treatment with β-carotene, were significantly suppressed by the RAR pan-antagonist. This suggests treatment with β-carotene enhanced early osteoblastic differentiation, at least in part via RAR signaling. These results indicate that a combination of isoflavones and β-carotene may be useful for maintaining a positive balance of bone turnover by inducing osteoblast differentiation.

Extracellular matrix production and degradation by bone cells are critical steps in bone metabolism. Mutations of the gene encoding MMP-2, an extracellular matrix-degrading enzyme, are associated with a human genetic disorder characterized by subcutaneous nodules, arthropathy, and focal osteolysis. It is not known how the loss of MMP-2 function results in the pathology. Here, we show that Mmp2(-/-) mice exhibited opposing bone phenotypes caused by an impaired osteocytic canalicular network. Mmp2(-/-) mice showed decreased bone mineral density in the limb and trunk bones but increased bone volume in the calvariae. In the long bones, there was moderate disruption of the osteocytic networks and reduced bone density throughout life, whereas osteoblast and osteoclast function was normal. In contrast, aged but not young Mmp2(-/-) mice had calvarial sclerosis with osteocyte death. Severe disruption of the osteocytic networks preceded osteocyte loss in Mmp2(-/-) calvariae. Successful transplantation of wild-type periosteum restored the osteocytic canalicular networks in the Mmp2(-/-) calvariae, suggesting local roles of MMP-2 in determining bone phenotypes. Our results indicate that MMP-2 plays a crucial role in forming and maintaining the osteocytic canalicular network, and we propose that osteocytic network formation is a determinant of bone remodeling and mineralization.

PGE2 acts as a potent stimulator of bone resorption in several disorders including osteoarthritis and periodontitis. Three PGE synthases (PGES) were isolated for PGE2 production, but which PGES has the major role in inflammatory bone resorption is still unclear. In this study, we examined the role of PGE2 in LPS-induced bone resorption using membrane-bound PGES (mPGES)-1-deficient mice (mPges1−/−). In osteoblasts from wild-type mice, PGE2 production was greatly stimulated by LPS following the expression of cyclooxygenase 2 and mPGES-1 mRNA, whereas no PGE2 production was found in osteoblasts from mPges1−/−. LPS administration reduced the bone volume in wild-type femur that was associated with an increased number of osteoclasts. In mPges1−/−, however, LPS-induced bone loss was reduced. We next examined whether mPGES-1 deficiency could alter the alveolar bone loss in LPS-induced experimental periodontitis. LPS was injected into the lower gingiva and bone mineral density of alveolar bone was measured. LPS induced the loss of alveolar bone in wild-type, but not in mPges1−/− mice, suggesting an mPGES-1 deficiency resistant to LPS-induced periodontal bone resorption. To understand the pathway of LPS-induced PGE2 production in osteoblast, we used C3H/HeJ mice with mutated tlr4. Osteoblasts from C3H/HeJ mice did not respond to LPS, and PGE2 production was not altered at all. LPS-induced bone loss in the femur was also impaired in C3H/HeJ mice. Thus, LPS binds to TLR4 on osteoblasts that directly induce mPGES-1 expression for PGE2 synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may provide a new target for the treatment of inflammatory bone disease.

We report the fabrication of AlGaN/GaN high electron mobility transistor (HEMT) with high breakdown voltage by employing the metal-insulator-semiconductor (MIS) gate structure. SiO2, SiN, and TiO2 were used for the insulators. The gate leak current was significantly reduced by employing the MIS structure, and the breakdown voltage characteristics were improved. The breakdown voltage of the MIS–HEMTs increased non-linearly with the increase of gate-drain length Lgd. The TiO2 insulator exhibited highest breakdown voltage of 2 kV with the on-resistance of 15.6 mΩ cm2 for Lgd = 28 μm. On the other hand, the breakdown voltage and on-resistance for SiN MIS–HEMT were found to be 1.7 kV and 6.9 mΩ cm2, respectively. We demonstrated that AlGaN/GaN MIS–HEMTs are promising not only for high speed applications but also for high power switching applications.

Low-turnover bone disease is one of the bone abnormalities observed in patients with chronic kidney disease (CKD) and is recognized to be associated with low serum parathyroid hormone (PTH) level and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood as renal dysfunction progresses in CKD patients. A recent in vitro study using an osteoblastic cell culture system suggests that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on the progression of low bone turnover have not been elucidated. In the present study, we produced rats with low bone turnover by performing parathyroidectomy (PTX) and fed these rats a diet containing indole, a precursor of IS, to elevate blood IS level from indole metabolism. Bone metabolism was evaluated by measuring histomorphometric parameters of secondary spongiosa of the femur. Histomorphometric analyses revealed significant decreases in both bone formation-related parameters and bone resorption-related parameters in PTX rats. In indole-treated PTX rats, further decreases in bone formation-related parameters were observed. In addition, serum alkaline phosphatase activity, a bone formation marker, and bone mineral density of the tibia tended to decrease in indole-treated PTX rats. These findings strongly suggest that IS exacerbates low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH.

Background— Interstitial collagen plays a crucial structural role in arteries. Matrix metalloproteinases (MMPs), including MMP-13/collagenase-3, likely contribute to collagen catabolism in atherosclerotic plaques. Methods and Results— To test the hypothesis that a specific MMP-collagenase influences the development and structure of atherosclerotic plaques, this study used atherosclerosis-susceptible apolipoprotein E–deficient mice that lack MMP-13/collagenase-3 ( Mmp-13 −/− /apoE −/− ) or express wild-type MMP-13/collagenase-3 ( Mmp-13 +/+ /apoE −/− ). Both groups consumed an atherogenic diet for 5 (n=8) or 10 weeks (n=9). Histological analyses of the aortic root of both groups revealed similar plaque size and accumulation of smooth muscle cells (a collagen-producing cell type) and macrophages (a major source of plaque collagenases) after 5 and 10 weeks of atherogenic diet. By 10 weeks, the plaques of Mmp-13 −/− /apoE −/− mice contained significantly more interstitial collagen than those of Mmp-13 +/+ /apoE −/− mice ( P Mmp-13 +/+ /apoE −/− mice versus those from Mmp-13 −/− /apoE −/− mice. Conclusions— These data support the hypothesis that MMP-13/collagenase-3 plays a vital role in the regulation and organization of collagen in atherosclerotic plaques.

Prostaglandin E (PGE)2 produced by osteoblasts acts as a potent stimulator of bone resorption. Inflammatory bone loss is accompanied by osteoclast formation induced by bone-resorbing cytokines, but the mechanism of PGE2 production and bone resorption in vivo is not fully understood. Using cytosolic phospholipase A2alpha (cPLA2alpha)-null mice, we examined the role of cPLA2alpha in PGE2 synthesis and bone resorption. In bone marrow cultures, interleukin (IL)-1 markedly stimulated PGE2 production and osteoclast formation in wild-type mice, but not in cPLA2alpha-null mice. Osteoblastic bone marrow stromal cells induced the expression of cyclooxygenase (COX)-2 and membrane-bound PGE2 synthase (mPGES) in response to IL-1 and lipopolysaccharide (LPS) to produce PGE2. Osteoblastic stromal cells collected from cPLA2alpha-null mice also induced the expression of COX-2 and mPGES by IL-1 and LPS, but could not produce PGE2 due to the lack of arachidonic acid release. LPS administration to wild-type mice reduced femoral bone mineral density by increased bone resorption. In cPLA2alpha-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2alpha plays a key role in PGE production by osteoblasts and in osteoclastic bone resorption, and suggest a new approach to inflammatory bone disease by inhibiting cPLA2alpha.

We examined the effects of heptamethoxyflavone (HMF), a citrus flavonoid on inflammatory bone resorption. HMF suppressed the osteoclast formation and PGE2 production induced by IL-1. In mouse calvarial organ cultures, HMF attenuated the bone resorption elicited by LPS. HMF suppressed bone resorption in the mandibular alveolar bone. HMF may protect against inflammatory bone loss such as periodontal disease.

Background: Carboranes (dicarba- closo -dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hydrophobicity. Applications of the unique structural and chemical properties offered by icosahedral carboranes in boron neutron capture therapy have received increasing attention over the past 30 years. However, these features of carboranes may allow another application as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with receptors. Results: We have designed candidate estrogen-receptor-binding compounds having carborane as a hydrophobic skeletal structure and synthesized them. The most potent compound bearing a carborane cage exhibited activity at least 10-fold greater than that of 17β-estradiol in the luciferase reporter gene assay. Estrogen receptor-α-binding data for the compound were consistent with the results of the luciferase reporter gene assay. The compound also showed potent in vivo effects on the recovery of uterine weight and bone loss in ovariectomized mice. Conclusion: Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-α ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.

Prostaglandin E(2) (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2.) In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.

Corrosion of NiMo 2 B 2 -dispersed Ni-based alloy containing Co, Mn, Cr, Fe or Cu was examined by measuring the mass loss and the corrosion potential in 6 mass%HNO 3 aqueous solution and by metallography. The corrosion was accelerated by addition of Co or Mn while it was retarded by addition of Cr, Fe or Cu. In particular, the addition of Cu greatly improved the corrosion resistance. The corrosion proceeded by a mechanism in which the Ni-matrix phase worked as anode while the NiMo 2 B 2 phase worked as cathode. The addition of Cu shifted the corrosion potential of the Ni-matrix phase to the noble side by about 15 mV, and consequently the difference in the corrosion potential between the Ni-matrix phase and the NiMo 2 B 2 phase decreased, As a result the preferential corrosion of the Ni-matrix phase was extremely retarded.

本研究は細菌の呼吸に着目し, 細菌培養溶液中の酸素濃度を測定することが可能な溶存酸素測定装置を用いた, 歯周病原性細菌であるActinobacillus actinomycetemcomitans (以下A. a.) の各種抗生物質に対する感受性の判定法を検討した。通性嫌気性グラム陰性菌であるA. a. は, 嫌気環境下および好気環境下のいずれの培養条件においても類似した増殖傾向を示し, A. a. が高い感受性を示す抗生物質であるテトラサイクリン, ミノサイクリンの存在下で増殖が有意に抑制された。さらに, 好気環境下で培養したA. a. の培養液中の溶存酸素量を溶存酸素測定装置により経時的に測定して酸素消費を検討した。培養液中の溶存酸素量はA. a. の総菌数に比例して減少し, A. a. による酸素消費が示された。また, これらの酸素消費はテトラサイクリンおよび, ミノサイクリンの濃度に依存して有意に抑制されたが, A. a. が感受性を示さない抗生物質であるバシトラシンおよびバンコマイシンでは酸素消費量に変化が認められなかった。以上の結果から, 溶存酸素測定装置を用いた薬剤感受性試験は歯周病原性の通性嫌気性菌であるA. a. に対して有用であり, 抗生物質の効果が迅速に判定できることが示唆された。

The dependence of DC operating characteristics on the device dimensions in AlGaN/GaN HEMTs is systematically obtained varying the device parameters in relatively wide range. The maximum transconductance gm,max and the maximum drain current ID,max depend on both the source-gate distance LSG and the gate length LG rather than LG only, and proportional to (LSG+LG)–0.5, which is different from the case of the GaAs or Si FET model. Influence of the source-gate distance LSG on the DC characteristics of AlGaN/GaN high electron mobility transistors is discussed. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The normally off operation of AlGaN/GaN heterojunction field effect transistor (HFET) devices with a p-type InGaN cap layer under a gate electrode was demonstrated. The threshold gate voltage VGth was 0.5 V, and the maximum transconductance gm was about 120 mS/mm. The maximum drain current IDmax was more than 210 mA/mm. RF characteristics were also measured, and it was found that fT is 2.1 GHz and fmax is 6.4 GHz when the gate length is 2 µm.

Estrogen deficiency caused by ovariectomy (OVX) results in a marked bone loss due to stimulated bone resorption by osteoclasts. During our investigations of the pathogenesis of bone loss in estrogen deficiency, we found that OVX selectively stimulates B-lymphopoiesis which results in marked accumulation of B220-positive pre-B cells in mouse bone marrow. To examine the possible correlation between stimulated B-lymphopoiesis and bone loss, 8-week-old female mice were treated with interleukin (IL) 7, which stimulates B-lymphopoiesis in bone marrow. We also examined bone mass in IL-7 receptor-knockout mice that exhibit marked suppression of B-lymphopoiesis in the bone marrow. The increased B-lymphopoiesis induced by IL-7 administration resulted in marked bone loss by stimulation of osteoclastic bone resorption in mice with intact ovarian function. The changes in both B-lymphopoiesis and bone mass in IL-7-treated female mice were similar to those in age-matched OVX mice. In contrast, the trabecular bone volume of the femur was greatly increased in both female and male IL-7 receptor-knockout mice when compared with the respective wild-type and heterozygous littermates. These results show that the perturbation of B-lymphopoiesis in the bone marrow is closely linked to the change in bone mass. We propose here that the increased B-lymphopoiesis due to estrogen deficiency is involved in the mechanism of stimulated bone resorption.

We examined the effects of β-cryptoxanthin, a typical carotenoid, on inflammatory periodontitis. β-Cryptoxanthin suppressed lipopolysaccharide (LPS)-induced osteoclast formation in co-cultures of bone marrow cells and osteoblasts. In a mouse model of periodontitis, it suppressed bone resorption in the mandibular alveolar bone in vitro and restored alveolar bone loss induced by LPS in vivo. β-Cryptoxanthin might protect against periodontal disease.

We investigated the effects of equol on adipogenesis by measuring lipid accumulation and analyzing the change in adipocyte-related gene expression in MC3T3-L1 cells. Treatment with 10 µM equol tended to increase adipocyte-related gene expression, whereas 100 µM equol reduced lipid accumulation and suppressed the expression of these genes and proteins. Our results suggest that equol regulated adipogenesis in a bi-phasic fashion.

Effects of bone morphogenetic protein (BMP)-12 and BMP-13, new members of the BMP family which belong to the transforming growth factor (TGF)-β superfamily, on terminal differentiation of myoblasts were examined in C2C12 and L-6 myoblasts. When the myoblasts were cultured with BMP-12 or BMP-13, the expression of the myosin heavy chain and the formation of multinucleated myotubes mRNA in L-6 cells. The inhibitory effects of BMP-12 and BMP-13 on myogenic differentiation were similar to the effects of BMP-2, though their potencies were lower than BMP-2. Unlike BMP-2, neither BMP-12 nor BMP-13 induced alkaline phosphatase activity in C2C12 myoblasts. The differences in the biological activities of these new BMPs suggest that the intracellular signalling pathway used by BMP-12 and BMP-13 differs from that of BMP-2.

Bombyx mori silk fibroin (SF) shows remarkably earlier calcification than bovine serum albumin, indicating advantage of the SF scaffold for bone regeneration. We provide evidence for the first time, that SF not only activate early differentiation markers of osteoblasts, but also activate expression of the late differentiation markers.

We have invented a mouse model of periodontitis associated with alveolar bone loss induced by lipopolysaccharide. Ovariectomized (OVX) animals are widely used as a model for osteoporosis due to estrogen deficiency. To define the relationship between periodontitis and osteoporosis, we examined the influence of estrogen deficiency on the mouse alveolar bone mass. In OVX mice, bone loss was detected not only in the femur, but also in the alveolar bone, indicating that estrogen deficiency could induce resorption in alveolar bone. In experiments using a combination of osteoporosis and periodontitis models, OVX significantly enhanced the alveolar bone loss in the model of periodontitis. Therefore, postmenopausal osteoporosis may enhance the risk of periodontitis associated with inflammatory alveolar bone resorption.

Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) ligand, regulates nerve-related pain-sensitive signals, inflammation, and cancer growth. Capsaicin suppresses interleukin-1-induced osteoclast differentiation, but its roles in bone tissues and bone diseases are not known. This study examined the effects of capsaicin on inflammatory bone resorption and prostaglandin E (PGE) production induced by lipopolysaccharide (LPS) in vitro and on bone mass in LPS-treated mice in vivo. Capsaicin suppressed osteoclast formation, bone resorption, and PGE production induced by LPS in vitro. Capsaicin suppressed the expression of cyclooxygenase-2 (COX-2) and membrane-bound PGE synthase-1 (mPGES-1) mRNAs and PGE production induced by LPS in osteoblasts. Capsaicin may suppress PGE production by inhibiting the expression of COX-2 and mPGES-1 in osteoblasts and LPS-induced bone resorption by TRPV1 signals because osteoblasts express TRPV1. LPS treatment markedly induced bone loss in the femur in mice, and capsaicin significantly restored the inflammatory bone loss induced by LPS in mice. TRPV1 ligands like capsaicin may therefore be potentially useful as clinical drugs targeting bone diseases associated with inflammatory bone resorption.

Nobiletin, a polymethoxy flavonoid, prevents cancer and inflammation, but the roles of nobiletin in bone are unclear. We examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice in vivo. In vitro, nobiletin suppressed osteoclast formation and bone resorption induced by interleukin (IL)-1. Nobiletin suppressed the expression of cyclooxygenase-2, NFκB-dependent transcription, and prostaglandin E (PGE) production induced by IL-1 in osteoblasts. OVX mice showed severe bone loss in the femur by increased bone resorption due to estrogen deficiency, and nobiletin significantly restored the bone mass. Nobiletin could be beneficial to bone health in postmenopausal women. Keywords:: polymethoxy flavonoid, bone resorption, osteoporosis

Bone resorption is regulated by various cytokines. In postmenopausal osteoporosis, bone loss due to estrogen deficiency is closely related to the production of bone-resorbing cytokine. Especially, the increased production of IL-1, IL-6 and TNF-α could induce the expression of RANKL in bone tissues to enhance osteoclastogenesis. Relationship between estrogen deficiency and various cytokines is important to clarify the pathogenesis of postmenopausal osteoporosis.

Several neurodegenerative diseases involve the selective damage of neuron cells resulting from the accumulation of amyloid fibril formation. Considering that the formation of amyloid fibrils as well as their precursor oligomers is cytotoxic, the agents that prevent the formation of oligomers and/or fibrils might allow the development of a novel therapeutic approach to neurodegenerative diseases. Here, we show pyrroloquinoline quinone (PQQ) inhibits the amyloid fibril formation of the amyloid proteins, amyloid beta (1-42) and mouse prion protein. The fibril formation of mouse prion protein in the presence of PQQ was dramatically prevented. Similarly, the fibril formation of amyloid beta (1-42) also decreased. With further advanced pharmacological approaches, PQQ may become a leading anti-neurodegenerative compound in the treatment of neurodegenerative diseases.

Prostaglandin E(2) is a crucial mediator to maintain physiological homeostasis and several disease progression. In this article, we summarized the roles of PGE(2) in bone resorptive metastatic model using B16 melanoma. An antagonist of EP4, a receptor subtype for PGE(2), suppressed RANKL expression in osteoblast and following osteoclast formation that was induced by B16, suggesting cancer induced bone resorption mediate PGE(2) production in host osteoblast is a key role of cancer metastasis to bone.

Matrix metalloproteinases (MMPs) are members of a family of zinc-dependent proteolytic enzymes. Several of the MMPs are expressed at high levels in bone and cartilage in mammals including humans and mice and are capable of cleaving native, undenatured collagens with long uninterrupted triple helices; these MMPs therefore potentially function as collagenases in vivo. Several MMPs expressed in the skeleton appear to function in endochondral ossification during embryonic development and in modeling and remodeling of bone postnatally and later in life. Different functions of MMPs have been elucidated through observations of spontaneous mutations in MMP genes in humans and of targeted mutations in Mmp genes and collagen (substrate) genes in mice. Potential mechanisms to account for effects of these mutations are considered in this review.

Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects.

We examined the effects of prostaglandin E (PGE) receptor subtype EP4 antagonist on bone metastasis of cancer to clarify PGE’s role in bone metastasis. Metastatic regions were detected in femurs accompanying severe bone loss in mice injected with B16 malignant melanoma cells. Administration of EP4 antagonist restored the bone loss induced by B16 melanoma. Adding B16 cells induced osteoclast formation in the coculture of bone marrow cells and osteoblasts without any exogenous bone-resorbing factor, and EP4 antagonist completely suppressed the osteoclast formation induced by B16 cells. Therefore, EP4 antagonist is a possible candidate for the therapy of bone metastasis of cancer.

We report the fabrication of AlGaN/GaN high electron mobility transistor (HEMT) with high breakdown voltage by employing the metal-insulator-semiconductor (MIS) gate structure. SiO 2 , SiN, and TiO 2 were used for the insulators. The gate leak current was significantly reduced by employing the MIS structure, and the breakdown voltage characteristics were improved. The breakdown voltage of the MIS-HEMTs increased non-linearly with the increase of gate-drain length L gd . The TiO 2 insulator exhibited highest breakdown voltage of 2 kV with the on-resistance of 15.6 mΩ cm 2 .for L gd = 28 μm. On the other hand, the breakdown voltage and on-resistance for SiN MIS-HEMT were found to be 1.7 kV and 6.9 mΩ cm 2 , respectively. We demonstrated that AlGaN/GaN MIS-HEMTs are promising not only for high speed applications but also for high power switching applications.

Aromatase converts androgen to estrogen as the sole enzyme that related bone metabolism as well as gonadal-genesis. We previously discovered aromatase-knockout (ArKO) mice showed bone loss that associated with increasing bone resorption was seen in both female and male mice. This is suggesting essential roles of estrogen for bone metabolism in both of gender. When male ArKO mice were orchidectomized (ORX) to induce a complete deficiency of both estrogen and androgen, ORX/ArKO showed severe osteopenia. The complexities for use of estrogen and androgen in bone metabolisms may have distinct or synergistic roles of bone turnover in female and male mice before/after reaching to sexual maturity.

MMPs, which degrade components of the ECM, have roles in embryonic development, tissue repair, cancer, arthritis, and cardiovascular disease. We show that a missense mutation of MMP13 causes the Missouri type of human spondyloepimetaphyseal dysplasia (SEMD(MO)), an autosomal dominant disorder characterized by defective growth and modeling of vertebrae and long bones. Genome-wide linkage analysis mapped SEMD(MO) to a 17-cM region on chromosome 11q14.3-23.2 that contains a cluster of 9 MMP genes. Among these, MMP13 represented the best candidate for SEMD(MO), since it preferentially degrades collagen type II, abnormalities of which cause skeletal dysplasias that include Strudwick type SEMD. DNA sequence analysis revealed a missense mutation, F56S, that substituted an evolutionarily conserved phenylalanine residue for a serine in the proregion domain of MMP13. We predicted, by modeling MMP13 structure, that this F56S mutation would result in a hydrophobic cavity with misfolding, autoactivation, and degradation of mutant protein intracellularly. Expression of wild-type and mutant MMP13s in human embryonic kidney cells confirmed abnormal intracellular autoactivation and autodegradation of F56S MMP13 such that only enzymatically inactive, small fragments were secreted. Thus, the F56S mutation results in deficiency of MMP13, which leads to the human skeletal developmental anomaly of SEMD(MO).

Recent technical advance for making of gene modified mice includes gene targeting and transgenic mice are clarify the biological function of its targeted molecules. The evidence from gene modified mice on sex-steroid hormones may contribute to develop clinical drugs for osteoporosis treatment especially. Gene deficient mice of the sole enzyme for estrogen synthesis (aromatase), estrogen receptor and androgen receptor deficient mice have great potential to elucidate further mechanisms of pathogenesis of osteoporosis.