Updated on 2026/06/16

写真a

 
CHIBA Norika
 
Organization
Research Field in Dentistry, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Health Research Course Developmental Medicine Assistant Professor
Title
Assistant Professor
Degree
(2007.4 Nagoya University)
(2003.3 Nagoya University)
(2001.3 Shizuoka University)

Research Interests

  • Osteoimmunology

  • Respiratory infectious diseases

  • Allergy

  • Immunology

Research Areas

Immunology, Immunology, Molecular biology

Research History

  • 2017.9    Kagoshima University   Research Field in Dentistry, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Health Research Course Developmental Medicine   Assistant Professor

Studying abroad experiences

  • 2009.1 - 2017.8   シダースサイナイメディカルセンター（米国）（Cedars-Sinai Medical Center, US）   博士研究員のちにプロジェクト研究員

 

Papers

  • Ohnishi T., Nagasawa Y., Misaki T., Chiba N., Matsuguchi T. .  Differential urinary IgG fragmentation in diabetes and IgA nephropathy .  Clinical and Experimental Nephrology30 ( 3 ) 489 - 497   2026.3

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    Language：Japanese   Publisher：Clinical and Experimental Nephrology  

    Background: Proteinuria is a key marker of chronic kidney disease, notably in diabetic nephropathy (DN) and IgA nephropathy (IgAN). This study examined urinary IgG fragmentation and its link to disease progression. Methods: Urinary IgG fragments were analyzed via western blot in diabetic mice and human subjects (controls: n = 7; diabetics: n = 14; IgAN: n = 15). Mouse and human IgG cleavage with renal tubular and glomerular fractions was performed in the presence or absence of protease inhibitors. Urinary cathepsin B activity was also measured. Results: In diabetic mice, a 31-kDa IgG fragment appeared in the urine before the onset of albuminuria. This process was mediated by cathepsin D in the tubular fraction. Analysis of human subjects showed that fragmented IgG, especially the 47 kDa fragment, was increased in the urine of diabetic patients and correlated with elevated glycated hemoglobin (HbA1c) levels, but not in IgAN patients. Cathepsin B generated the IgG fragment by the tubular fraction, and its urinary activity was lower in IgAN patients than in diabetics. Conclusion: Distinct patterns of IgG fragmentation and cathepsin B activity in DN versus IgAN suggest urinary IgG fragments may serve as early biomarkers and reflect disease-specific proteolytic pathways.

    DOI： 10.1007/s10157-025-02805-6

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  • Yutoku M., Fujita K., Chiba N., Tada R., Ohnishi T., Sugimura M., Matsuguchi T. .  Early Growth Response 1 Plays an Essential Role in Proinflammatory and Osteoclastogenic Activities of Lipopolysaccharide-Stimulated Osteoblasts .  FASEB Journal39 ( 7 ) e70532   2025.4

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    Language：Japanese   Publisher：FASEB Journal  

    Lipopolysaccharide (LPS) of Gram-negative bacteria in oral plaque is the major cause of periodontal disease. It is involved in the induction of inflammation and alveolar bone resorption at least partly by directly reacting to Toll-like receptor (TLR) 4 on osteoblasts. LPS induces osteoblasts to express proinflammatory cytokines, chemokines, and prostaglandins, as well as macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), which directly activate adjacent osteoclasts toward bone resorption. However, the regulator mechanisms have not been fully revealed at the molecular level. Here, we have demonstrated that LPS rapidly induces expression of early growth response 1 (EGR1), a zinc-finger transcription factor, and analyzed its physiological functions in osteoblasts. In both primary osteoblasts and an osteoblast cell line, LPS induced expression of EGR1 mRNA and protein within 30 min and 60 min, respectively, which were relatively slower than in macrophages. Inhibition of EGR1 by siRNA significantly inhibited LPS-induced mRNA expression of the tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokines, cyclooxygenase-2 (COX2), matrix metalloproteinase-13 (MMP13), M-CSF, and RANKL in osteoblasts. Moreover, forced overexpression of EGR1 by the inducible expression system was sufficient to increase mRNA expression levels of TNF, IL-6, COX2, MMP13, and RANKL without LPS stimulation. As for the intracellular signal transduction, LPS-induced EGR1 expression in osteoblasts was dependent on the unique c-Jun N-terminal kinase (JNK)–extracellular signal-regulated kinase (ERK) activation pathway. Our data suggest an essential role of EGR1 in osteoblast responses to LPS-inducing tissue inflammation and osteolysis, providing new insights into the pathogenesis of periodontal disease.

    DOI： 10.1096/fj.202402623R

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  • Chiba Norika, Ohnishi Tomokazu, Matsuguchi Tetsuya .  低酸素誘導因子1αは、低酸素下の肥満細胞におけるリポ多糖誘導性IL-13およびIL-33発現を増強する(Hypoxia-Inducible Factor 1 Alpha Potentiates Lipopolysaccharide-Induced Expression of IL-13 and IL-33 in Mast Cells Under Hypoxia) .  Microbiology and Immunology69 ( 4 ) 247 - 255   2025.4

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    Language：English   Publisher：John Wiley & Sons Australia, Ltd  

    肥満細胞(MC)におけるリポ多糖(LPS)誘導性サイトカイン発現に対する低酸素の影響を検討した。マウスMC株MC/9を用い、通常酸素濃度と低酸素条件下でLPS刺激を行い、サイトカインのmRNA発現やタンパク質産生を解析した。また、低分子干渉RNA(siRNA)によるHIF-1αのノックダウンを行い、その役割を確認した。その結果、LPSはMC/9において、Il4、Il6、Il13、Il33、Tnf、TslpのmRNA発現を誘導した。低酸素環境下では、LPSによるIl13およびIl33のmRNA発現が有意に増強されたが、他のサイトカインの発現には影響を及ぼさなかった。さらに、siRNAによるHIF-1αのノックダウンにより、低酸素によるIl13およびIl33の発現増強効果は減少した。

  • Norika Chiba, Tomokazu Ohnishi, Tetsuya Matsuguchi .  Hypoxia‐Inducible Factor 1 Alpha Potentiates Lipopolysaccharide‐Induced Expression of IL‐13 and IL‐33 in Mast Cells Under Hypoxia .  Microbiology and Immunology69 ( 4 ) 247 - 255   2025.2Reviewed

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    ABSTRACT

    Lipopolysaccharide (LPS) is an exacerbating factor for allergic airway inflammation at least partly due to the activation of mast cells (MCs). LPS stimulates MCs to express both pro‐inflammatory and type 2 cytokines, among which interleukin (IL)‐13 is essential for the generation of allergic diseases. LPS also induces the expression of “alarmins” such as IL‐25, IL‐33, and thymic stromal lymphopoietin (TSLP) from various cell types including epithelial cells, and increased serum IL‐33 levels were reported to correlate with disease severity of asthma. MCs reside in peripheral tissues where the oxygen concentration is significantly lower than that in the air and further decreased by inflammation and bronchoconstriction in asthma. However, the effects of hypoxia on LPS‐induced cytokine expression in MCs have not been fully elucidated. Here we show that LPS induces Il4, Il6, Il13, Il33, Tnf, and Tslp mRNAs in MCs. Notably, hypoxia robustly enhanced expressions of Il13 and Il33, but not the other cytokines in LPS‐stimulated MCs. We also found that this promotive effect is dependent on the presence of hypoxia‐inducible factor (HIF) 1α protein. Our study will provide new insight on the role of MCs in the LPS‐associated pathogenesis of allergic diseases.

    DOI： 10.1111/1348-0421.13202

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  • Mardiyantoro F., Chiba N., Seong C.H., Tada R., Ohnishi T., Nakamura N., Matsuguchi T. .  Two-sided function of osteopontin during osteoblast differentiation .  Journal of Biochemistry177 ( 2 ) 121 - 131   2025.2

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    Language：Japanese   Publisher：Journal of Biochemistry  

    Osteopontin (OPN) is expressed in various cell types including osteoblasts. OPN expression level is robustly increased during osteoblast differentiation. Although OPN was initially found as a secretory protein (sOPN), recent reports identified the intracellular isoform of OPN (iOPN). Distinct functions of each OPN isoform in osteoblasts, however, are not well established. Here, using the Tet-On inducible expression system, we examined the role of each OPN isoform during osteoblast differentiation. Induced overexpression of wild type OPN (wtOPN), which includes both sOPN and iOPN, significantly increased matrix mineralization and osteogenic marker gene expression during osteogenic differentiation induced by either ascorbic acid or bone morphogenetic protein (BMP) 9. In contrast, these osteogenic differentiation processes were significantly inhibited by the specific overexpression of iOPN. Furthermore, the addition of recombinant OPN or neutralizing anti-OPN antibody to the culture medium exerted promotive or inhibitory effect on osteoblast differentiation, respectively. These data strongly indicate that iOPN exerts inhibitory effects on osteoblast differentiation, whereas sOPN exerts positive effects. We also found that the secretion process of OPN is positively regulated by c-Jun N-terminal kinase (JNK) activity in osteoblasts.

    DOI： 10.1093/jb/mvae080

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  • Mardiyantoro Fredy, Chiba Norika, Seong Chang-Hwan, Tada Ryohei, Ohnishi Tomokazu, Nakamura Norifumi, Matsuguchi Tetsuya .  骨芽細胞分化におけるオステオポンチンの二面的な機能(Two-sided function of osteopontin during osteoblast differentiation) .  The Journal of Biochemistry177 ( 2 ) 121 - 131   2025.2

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    Language：English   Publisher：(公社)日本生化学会  

    骨形成に関与するオステオポンチン(OPN)の細胞内型(iOPN)と分泌型(sOPN)の機能を分離し、骨芽細胞分化への影響を解析した。Tet-On誘導系を用いてOPNの各アイソフォームをMC3T3-E1細胞に過剰発現させた結果、sOPNは石灰化と骨形成マーカー遺伝子の発現を促進する一方、iOPNはそれらを抑制した。さらに、培地中に組換え型OPNを添加すると骨芽細胞の分化が促進され、逆にOPNの中和抗体を添加すると分化が抑制された。また、JNK阻害によりOPN分泌が低下し、JNK活性がOPNの分泌制御に関与する可能性も示された。以上より、OPNアイソフォームのバランスが骨芽細胞分化を制御する鍵であると考えられた。

  • Norika Chiba, Ryohei Tada, Tomokazu Ohnishi, Tetsuya Matsuguchi .  TLR4/7-mediated host-defense responses of gingival epithelial cells. .  Journal of cellular biochemistry125 ( 7 ) e30576   2024.7Reviewed International journal

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    Gingival epithelial cells (GECs) are physical and immunological barriers against outward pathogens while coping with a plethora of non-pathogenic commensal bacteria. GECs express several members of Toll-like receptors (TLRs) and control subsequent innate immune responses. TLR4 senses lipopolysaccharide (LPS) while TLR7/8 recognizes single-strand RNA (ssRNA) playing important roles against viral infection. However, their distinct roles in GECs have not been fully demonstrated. Here, we analyzed biological responses of GECs to  LPS and CL075, a TLR7/8 agonist. GE1, a mouse gingival epithelial cell line, constitutively express TLR4 and TLR7, but not TLR8, like primary skin keratinocytes. Stimulation of GE1 cells with CL075 induced cytokine, chemokine, and antimicrobial peptide  expressions, the pattern of which is rather different from that with LPS: higher mRNA levels of interferon (IFN) β, CXCL10, and β-defensin (BD) 14 (mouse homolog of human BD3); lower levels of tumor necrosis factor (TNF), CCL5, CCL11, CCL20, CXCL2, and CX3CL1. As for the intracellular signal transduction of GE1 cells, CL075 rapidly induced significant AKT phosphorylation but failed to activate IKKα/β-NFκB pathway, whereas LPS induced marked IKKα/β-NFκB activation without significant AKT phosphorylation. In contrast, both CL075 and LPS induced rapid IKKα/β-NFκB activation and AKT phosphorylation in a macrophage cell line. Furthermore, specific inhibition of AKT activity abrogated CL075-induced IFNβ, CXCL10, and BD14 mRNA expression in GE1 cells. Thus, TLR4/7 ligands appear to induce rather different host-defense responses of GECs through distinct intracellular signaling mechanisms.

    DOI： 10.1002/jcb.30576

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  • Chang‐Hwan Seong, Norika Chiba, Mardiyantoro Fredy, Joji Kusuyama, Kiyohide Ishihata, Toshiro Kibe, Muhammad Subhan Amir, Ryohei Tada, Tomokazu Ohnishi, Norifumi Nakamura, Tetsuya Matsuguchi .  Early induction of Hes1 by bone morphogenetic protein 9 plays a regulatory role in osteoblastic differentiation of a mesenchymal stem cell line .  Journal of Cellular Biochemistry124 ( 9 ) 1366 - 1378   2023.8

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    Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    Abstract

    Bone morphogenic protein 9 (BMP9) is one of the most potent inducers of osteogenic differentiation among the 14 BMP members, but its mechanism of action has not been fully demonstrated. Hes1 is a transcriptional regulator with basic helix‐loop‐helix (bHLH) domain and is a well‐known Notch effector. In this study, we investigated the functional roles of early induction of Hes1 by BMP9 in a mouse mesenchymal stem cell line, ST2. Hes1 mRNA was transiently and periodically induced by BMP9 in ST2, which was inhibited by BMP signal inhibitors but not by Notch inhibitor. Interestingly, Hes1 knockdown in ST2 by siRNA increased the expression of osteogenic differentiation markers such as Sp7 and Ibsp and matrix mineralization in comparison with control siRNA transfected ST2. In contrast, forced expression of Hes1 by using the Tet‐On system suppressed the expression of osteogenic markers and matrix mineralization by BMP9. We also found that the early induction of Hes1 by BMP9 suppressed the expression of Alk1, an essential receptor for BMP9. In conclusion, BMP9 rapidly induces the expression of Hes1 via the SMAD pathway in ST2 cells, which plays a negative regulatory role in osteogenic differentiation of mesenchymal stem cells induced by BMP9.

    DOI： 10.1002/jcb.30452

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  • 大西 智和, 中村 利明, 嶋 香織, 野口 和行, 千葉 紀香, 松口 徹也 .  歯周炎によるSARS-CoV-2のプライミング因子であるTMPRSS2の歯肉発現増強(Periodontitis promotes gingival expression of TMPRSS2, a priming factor for SARS-CoV-2) .  Journal of Oral Biosciences Supplement2022   138 - 138   2022.9

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    Language：Japanese   Publisher：(一社)歯科基礎医学会  

  • Tomokazu Ohnishi, Toshiaki Nakamura, Kaori Shima, Kazuyuki Noguchi, Norika Chiba, Tetsuya Matsuguchi .  Periodontitis promotes the expression of gingival transmembrane serine protease 2 (TMPRSS2), a priming protease for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). .  Journal of oral biosciences64 ( 2 ) 229 - 236   2022.6International journal

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

    OBJECTIVES: The oral cavity is one of the main entry sites for SARS-CoV-2. Gingival keratinocytes express transmembrane serine protease 2 (TMPRSS2), responsible for priming the SARS-CoV-2 spike protein. We investigated whether periodontitis increased the expression of TMPRSS2. METHODS: To investigate gene expression in periodontitis, we analyzed the expression of specific genes from (1) the Gene Expression Omnibus (GEO) dataset of 247 human gingival tissues and (2) an experimentally-induced periodontitis mouse model. Human gingival tissues with or without periodontitis were immunohistochemically stained using an anti-TMPRSS2 antibody. Analysis of the TMPRSS2 promoter was performed using a ChIP-Atlas dataset. TMPRSS2 expression was detected in cultured human keratinocytes using quantitative reverse transcription (qRT)-PCR and Western blot analysis. RESULTS: GEO dataset analysis and an experimentally-induced periodontitis model revealed increased expression of TMPRSS2 in periodontitis gingiva. The keratinocyte cell membrane in periodontitis gingiva was strongly immunohistochemically stained for TMPRSS2. Using ChIP-Atlas and GEO datasets, we screened for transcription factors that bind to the TMPRSS2 promoter region. We found one candidate, estrogen receptor 1 (ESR1), highly expressed in periodontitis gingiva. Analysis of the GEO dataset revealed a correlation between ESR1 and TMPRSS2 expression in gingival tissues. An ESR1 ligand induced TMPRSS2 expression in cultured keratinocytes. CONCLUSIONS: Periodontitis increases TMPRSS2 expression in the cell membrane of gingival keratinocytes.

    DOI： 10.1016/j.job.2022.04.004

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  • Ohnishi Tomokazu, Nakamura Toshiaki, Shima Kaori, Noguchi Kazuyuki, Chiba Norika, Matsuguchi Tetsuya .  重症急性呼吸器症候群コロナウイルス2(SARS-CoV-2)に対するプライミングプロテアーゼとして働くtransmembrane serine protease 2(TMPRSS2)の歯肉での発現は歯周炎によって促進される(Periodontitis promotes the expression of gingival transmembrane serine protease 2(TMPRSS2), a priming protease for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)) .  Journal of Oral Biosciences64 ( 2 ) 229 - 236   2022.6

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    Language：English   Publisher：(一社)歯科基礎医学会  

    重症急性呼吸器症候群コロナウイルス2(SARS-CoV-2)のプライミングの原因となるtransmembrane serine protease 2(TMPRSS2)は歯肉の角化細胞で発現している。本研究では歯周炎によってTMPRSS2発現が増加するか調査した。Gene Expression Omnibus(GEO)データベースから、歯槽骨欠損の患者90名に由来する歯肉組織検体247件のデータセットを取得し解析した。実験的誘発歯周炎マウスモデルでの実験を行った。それらの解析と実験の結果、歯周炎を発症した歯肉ではTMPRSS2遺伝子の発現が増加した。歯周炎罹患・非罹患の被験者に由来する歯周組織を免疫組織化学に供したところ、歯周炎歯肉の角化細胞の細胞膜にTMPRSS2の強反応がみられた。ChIP-AtlasデータセットとGEOデータセットを利用し、TMPRSS2遺伝子のプロモーター領域に結合する転写因子を検索した結果、歯周炎歯肉で高発現しているエストロゲン受容体1(ESR1)が唯一の候補として同定され、歯肉組織におけるESR1発現とTMPRSS2発現は相関していることが示された。培養角化細胞ではESR1リガンドによりTMPRSS2発現が誘導された。以上から、歯肉角化細胞の細胞膜におけるTMPRSS2発現は歯周炎によって増加すると結論された。

  • Norika Chiba, Yukie Noguchi, Chang Hwan Seong, Tomokazu Ohnishi, Tetsuya Matsuguchi .  EGR1 plays an important role in BMP9-mediated osteoblast differentiation by promoting SMAD1/5 phosphorylation. .  FEBS letters596 ( 13 ) 1720 - 1732   2022.5International journal

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

    Bone morphogenetic proteins (BMPs) are essential regulators of skeletal homeostasis, and BMP9 is the most potently osteogenic among them. Here, we found that BMP9 and BMP2 rapidly induced early growth response 1 (EGR1) protein expression in osteoblasts through MEK/ERK pathway-dependent transcriptional activation. Knock-down of EGR1 using siRNA significantly inhibited BMP9-induced matrix mineralization and osteogenic marker gene expression in osteoblasts. Knock-down of EGR1 significantly reduced SMAD1/5 phosphorylation and inhibited the expression of their transcriptional targets in osteoblasts stimulated by BMP9. In contrast, forced EGR1 overexpression in osteoblasts enhanced BMP9-mediated osteoblast differentiation and SMAD1/5 phosphorylation. An intracellular association between EGR1 and SMAD1/5 was identified using immunoprecipitation assays. These results indicated that EGR1 plays an important role in BMP9-stimulated osteoblast differentiation by enhancing SMAD1/5 phosphorylation.

    DOI： 10.1002/1873-3468.14407

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  • Muhammad Subhan Amir, Norika Chiba, Chang Hwan Seong, Joji Kusuyama, Nahoko Eiraku, Tomokazu Ohnishi, Norifumi Nakamura, Tetsuya Matsuguchi .  HIF-1α plays an essential role in BMP9-mediated osteoblast differentiation through the induction of a glycolytic enzyme, PDK1. .  Journal of cellular physiology237 ( 4 ) 2183 - 2197   2022.4International journal

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

    Bone homeostasis is regulated by bone morphogenic proteins (BMPs), among which BMP9 is one of the most osteogenic. Here, we have found that BMP9 rapidly increases the protein expression of hypoxia-inducible factor-1α (HIF-1α) in osteoblasts under normoxic conditions more efficiently than BMP2 or BMP4. A combination of BMP9 and hypoxia further increased HIF-1α protein expression. HIF-1α protein induction by BMP9 is not accompanied by messenger RNA (mRNA) increase and is inhibited by the activation of prolyl hydroxylase domain (PHD)-containing protein, indicating that BMP9 induces HIF-1α protein expression by inhibiting PHD-mediated protein degradation. BMP9-induced HIF-1α protein increase was abrogated by inhibitors of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) kinase, indicating that it is mediated by PI3K-AKT signaling pathway. BMP9 increased mRNA expression of pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic enzyme, and vascular endothelial growth factor-A (VEGF-A), an angiogenic factor, in osteoblasts. Notably, BMP9-induced mRNA expression of PDK1, but not that of VEGF-A, was significantly inhibited by small interference RNA-mediated knockdown of Hif-1α. BMP9-induced matrix mineralization and osteogenic marker gene expressions were significantly inhibited by chemical inhibition and gene knockdown of either Hif-1α or Pdk-1, respectively. Since increased glycolysis is an essential feature of differentiated osteoblasts, our findings indicate that HIF-1α expression is important in BMP9-mediated osteoblast differentiation through the induction of PDK1.

    DOI： 10.1002/jcp.30752

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  • 千葉 紀香, 成 昌奐, 大西 智和, 松口 徹也 .  骨芽細胞分化におけるHypoxiaが及ぼす影響の解析(Hypoxia affects osteoblast differentiation) .  Journal of Oral Biosciences Supplement2021   327 - 327   2021.10

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    Language：Japanese   Publisher：(一社)歯科基礎医学会  

  • Tomokazu Ohnishi, Mitsuhiro Hisadome, Kusuyama Joji, Norika Chiba, Muhammad Subhan Amir, Takuro Kanekura, Tetsuya Matsuguchi .  Ultraviolet B irradiation decreases CXCL10 expression in keratinocytes through endoplasmic reticulum stress. .  Journal of cellular biochemistry122 ( 9 ) 1141 - 1156   2021.4International journal

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

    Ultraviolet radiation is one of the standard treatment selections for psoriasis. interferon (IFN)-γ and IFN-γ-induced CXCL10, which are highly expressed by keratinocytes in psoriasis lesion, are therapeutic targets for psoriasis. In this study, we found that ultraviolet B (UVB) irradiation inhibited IFN-γ signaling events, including STAT1 phosphorylation and induction of CXCL10 messenger RNA (mRNA) expression in keratinocytes. IFN-γ-induced expression of CXCL10 mRNA in HaCaT cells, a human keratinocyte cell line, and human epithelial keratinocytes were also inhibited by H2 O2 or endoplasmic reticulum (ER) stress inducers. Conversely, a mixture of antioxidants, Trolox and ascorbic acid, and the ER stress inhibitor salubrinal partially counteracted the inhibitory effect of UVB on IFN-γ-induced CXCL10 mRNA expression in HaCaT cells. We also found that UVB and ER stress reduced IFN-γ receptor 1 protein levels in the plasma membrane fraction of keratinocytes. These observations suggested that ER stress and the generation of reactive oxygen species are essential for the inhibitory effect of UVB on IFN-γ-induced CXCL10 mRNA in keratinocytes.

    DOI： 10.1002/jcb.29936

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  • Chang-Hwan Seong, Norika Chiba, Joji Kusuyama, Muhammad Subhan Amir, Nahoko Eiraku, Sachiko Yamashita, Tomokazu Ohnishi, Norifumi Nakamura, Tetsuya Matsuguchi .  Bone morphogenetic protein 9 (BMP9) directly induces Notch effector molecule Hes1 through the SMAD signaling pathway in osteoblasts. .  FEBS letters595 ( 3 ) 389 - 403   2020.12

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    Language：Japanese  

    Bone morphogenetic protein (BMP) 9 is one of the most osteogenic BMPs, but its mechanism of action has not been fully elucidated. Hes1, a transcriptional regulator with a basic helix-loop-helix (bHLH) domain, is a well-known effector of Notch signaling. Here, we find that BMP9 induces periodic increases of Hes1 mRNA and protein expression in osteoblasts, presumably through an autocrine negative feedback mechanism. BMP9-mediated Hes1 induction is significantly inhibited by an ALK inhibitor and overexpression of Smad7, an inhibitory Smad. Luciferase and chromatin immunoprecipitation assays revealed that two Smad binding sites in the 5' upstream region of the mouse Hes1 gene are essential for transcriptional activation by BMP9. Thus, our data indicate that BMP9 induces Hes1 expression in osteoblasts via the Smad signaling pathway.

    DOI： 10.1002/1873-3468.14016

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  • Nahoko Eiraku, Norika Chiba, Toshiaki Nakamura, Muhammad Subhan Amir, Chang-Hwan Seong, Tomokazu Ohnishi, Joji Kusuyama, Kazuyuki Noguchi, Tetsuya Matsuguchi .  BMP9 directly induces rapid GSK3-β phosphorylation in a Wnt-independent manner through class I PI3K-Akt axis in osteoblasts. .  FASEB journal : official publication of the Federation of American Societies for Experimental Biology33 ( 11 ) 12124 - 12134   2019.7Reviewed

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

    Bone morphogenetic protein (BMP)9 has been reported to be the most potent BMP to induce bone formation. However, the details of BMP9-transduced intracellular signaling remain ambiguous. Here, we have investigated signal transduction mechanisms of BMP9 in comparison to BMP2, another potent inducer of bone formation, in osteoblasts. In a mouse osteoblast cell line, BMP9 induced higher mRNA levels of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) than BMP2 within 2 h. Unlike BMP2, BMP9 induced rapid phosphorylation of glycogen synthase kinase 3-β (GSK3-β) and protein kinase B (Akt) and increased the cellular protein content of β-catenin. BMP9 moderately increased mRNA levels of several canonical Wingless-related integration site to lower degrees than BMP2. Furthermore, BMP9-induced GSK3-β phosphorylation was not inhibited by pretreatment with actinomycin D, cycloheximide, or Brefeldin A, indicating it is independent of Wnt protein secretion. BMP9-induced GSK3-β phosphorylation was abrogated by Akt or class I PI3K-specific inhibitors. Moreover, inactivation of GSK3-β by LiCl did not further promote ALP and Runx2 mRNA induction by BMP9 as significantly as that by BMP2. Notably, BMP9-induced GSK3-β phosphorylation was inhibited by small interfering RNA against endoglin and GIPC PDZ domain-containing family, member 1. Taken together, our present findings have indicated that BMP9 directly activates GSK3β-β-catenin signaling pathway through class I PI3K-Akt Axis in osteoblasts, which may be essential for the potent osteoinductive activity of BMP9.-Eiraku, N., Chiba, N., Nakamura, T., Amir, M. S., Seong, C.-H., Ohnishi, T., Kusuyama, J., Noguchi, K., Matsuguchi, T. BMP9 directly induces rapid GSK3-β phosphorylation in a Wnt-independent manner through class I PI3K-Akt axis in osteoblasts.

    DOI： 10.1096/fj.201900733RR

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  • Changfu Yao, Gianni Carraro, Bindu Konda, Xiangrong Guan, Takako Mizuno, Norika Chiba, Matthew Kostelny, Adrianne Kurkciyan, Gregory David, Jonathan L McQualter, Barry R Stripp .  Sin3a regulates epithelial progenitor cell fate during lung development .  Development144 ( 14 ) 2618 - 2628   2017.7Reviewed

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  • Magali Noval Rivas, Youngho Lee, Daiko Wakita, Norika Chiba, Jargalsaikhan Dagvadorj, Kenichi Shimada, Shuang Chen, Michael C Fishbein, Thomas JA Lehman, Timothy R Crother, Moshe Arditi .  CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract–Induced Murine Model of Kawasaki Disease .  Arthritis & Rheumatology69 ( 2 ) 410 - 421   2017.2Reviewed

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  • Magali Noval Rivas, Youngho Lee, Daiko Wakita, Norika Chiba, Jargalsaikhan Dagvadorj, Kenichi Shimada, Shuang Chen, Michael C Fishbein, Thomas J A Lehman, Timothy R Crother, Moshe Arditi .  CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease. .  Arthritis & rheumatology (Hoboken, N.J.)69 ( 2 ) 410 - 421   2017.2

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    OBJECTIVE: Kawasaki disease (KD) is the leading cause of acquired heart disease among children in developed countries. Coronary lesions in KD in humans are characterized by an increased presence of infiltrating CD3+ T cells; however, the specific contributions of the different T cell subpopulations in coronary arteritis development remain unknown. Therefore, we sought to investigate the function of CD4+ and CD8+ T cells, Treg cells, and natural killer (NK) T cells in the pathogenesis of KD. METHODS: We addressed the function of T cell subsets in KD development by using a well-established murine model of Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis. We determined which T cell subsets were required for development of KD vasculitis by using several knockout murine strains and depleting monoclonal antibodies. RESULTS: LCWE-injected mice developed coronary lesions characterized by the presence of inflammatory cell infiltrates. Frequently, this chronic inflammation resulted in complete occlusion of the coronary arteries due to luminal myofibroblast proliferation (LMP) as well as the development of coronary arteritis and aortitis. We found that CD8+ T cells, but not CD4+ T cells, NK T cells, or Treg cells, were required for development of KD vasculitis. CONCLUSION: The LCWE-induced murine model of KD vasculitis mimics many histologic features of the disease in humans, such as the presence of CD8+ T cells and LMP in coronary artery lesions as well as epicardial coronary arteritis. Moreover, CD8+ T cells functionally contribute to the development of KD vasculitis in this murine model. Therapeutic strategies targeting infiltrating CD8+ T cells might be useful in the management of KD in humans.

    DOI： 10.1002/art.39939

    PubMed

  • Samriddha Ray, Norika Chiba, Changfu Yao, Xiangrong Guan, Alicia M McConnell, Brian Brockway, Loretta Que, Jonathan L McQualter, Barry R Stripp .  Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection .  Stem cell reports7 ( 5 ) 817 - 825   2016.11Reviewed

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

  • Norika Chiba, Kenichi Shimada, Shuang Chen, Heather D. Jones, Randa Alsabeh, Anatoly V. Slepenkin, Ellena Peterson, Timothy R. Crother, and Moshe Arditi .  Mast cells play an important role in Chlamydia pneumonia lung infection by facilitating immune cell recruitment into the airway .  The Journal of Immunology194 ( 8 ) 3840 - 3851   2015.4Reviewed

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association of Immunologists  

  • Jupelli M, Shimada K, Chiba N, Slepenkin A, Alsabeh R, Jones HD, Peterson E, Chen S, Arditi M, Crother TR .  Chlamydia pneumonia infection in mice induces chronic lung inflammation, iBALT formation, and fibrosis. .  PLoS ONE   2013Reviewed

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

  • Lee YH, Schulte DJ, Shimada K, Chen S, Crother TR, Chiba N, Fishbein MC, Lehman TJA, Arditi M .  IL-1β is Crucial for Induction of Coronary Artery Inflammation in a Mouse Model of Kawasaki Disease. .  Circulation125 ( 12 ) 1542 - 1550   2012Reviewed

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

  • Crother TR, Ma J, Jupelli M, Chiba N, Chen S, Slepenkin A, Alsabeh R, Peterson E, Shimada K, Arditi M .  Plasmacytoid Dendritic Cells Play a Role for Effective Innate Immune Responses during Chlamydia pneumoniae Infection in Mice. .  PLoS ONE   2012Reviewed

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

  • Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AW, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M .  Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome During Apoptosis. .  Immunity36 ( 3 ) 401 - 414   2012Reviewed

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

  • Shimada K, Crother TR, Karlin J, Chen S, Chiba N, Rmanujan VK, Vergnes L, Ojcius DM, Arditi M .  Caspase-1 Dependent IL-1β Secretion Is Critical for Host Defense in a Mouse Model of Chlamydia pneumoniae Lung Infection. .  PLoS ONE   2011Reviewed

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

  • Chiba N., Kakimoto K., Masuda A., Matsuguchi T. .  Functional roles of Cot/Tpl2 in mast cell responses to lipopolysaccharide and FcεRI-clustering. .  Chiba N., Kakimoto K., Masuda A., Matsuguchi T.402 ( 1 ) 1 - 6   2010Reviewed

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

  • Matsuguhi T., Chiba N., Bandow K., Kakimoto K., Ohnishi T .  JNK activity is essential for Aft4 expression and late-stage osteoblast differentiation. .  Journal of Bone and Mineral Research24 ( 3 ) 398 - 410   2009Reviewed

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

  • Kasai T., Bandow K., Suzuki H., Chiba N., kakimoto K., Ohnishi T., Kawamoto S., Nagaoka E., Matsuguchi T. .  Osteoblast differentiation is functionally associated with decreased AMP kinase activity. .  Journal of Cellular Physiology221 ( 3 ) 740 - 749   2009Reviewed

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

  • Okamoto A., Ohnishi T., Bandow K., Kakimoto K., Chiba N., Maeda A., Fukunaga T., Miyawaki S., Matsuguchi T. .  Reduction of orthodontic tooth movement by experimental induced periodontal inflammation in mice. .  European Journal of Oral Science117 ( 3 ) 238 - 247   2009Reviewed

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

  • Chiba N., Masuda A., Yoshikai Y., and Matsuguchi T. .  Ceramide inhibits LPS-induced production of IL-5, IL-10, and IL-13 from mast cells. .  Journal of Cellular Physiology213 ( 1 ) 126 - 136   2007Reviewed

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

  • Musikacharoen T., Oguma A., Yoshikai Y., Chiba N., Masuda A., and Matsuguchi T. .  Interleukin-15 induces IL-12 receptor beta1 gene expression through PU.1 and IRF3 by targeting Chromatin remodeling. .  Blood105 ( 2 ) 711 - 720   2005Reviewed

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MISC

  • LPS刺激によるマスト細胞からのサイトカイン産生機構におけるセラミドの役割

    千葉紀香, 増田章男, 松口徹也

    アレルギー科   15 ( 3 )   220 - 227   2003

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    Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Presentations

  • 千葉紀香、大西智和、松口徹也   マスト細胞の活性化に低酸素環境が及ぼす影響の解析  

    第65回 歯科基礎医学会学術大会 

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    Event date： 2023.9

    Presentation type：Poster presentation  

  • 千葉紀香、大西智和、松口徹也   LPSによるマスト細胞のサイトカイン産生に低酸素が及ぼす選択的影響  

    第5回 南九州歯学会学術大会 

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    Event date： 2023.8

    Presentation type：Oral presentation (general)  

  • 千葉紀香、成昌奐、大西智和、松口徹也   EGR1はBMP9によるSMAD1/5活性化を増強して骨芽細胞分化を促進する  

    第64回 歯科基礎医学会学術大会 

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    Event date： 2022.9

    Presentation type：Poster presentation  

  • 千葉紀香、大西智和、松口徹也   EGR1はSMAD1/5リン酸化を増強して⾻芽細胞分化を促進する  

    第4回 南九州歯学会学術大会 

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    Event date： 2022.8

  • 千葉紀香、成昌奐、大西智和、松口徹也   骨芽細胞分化におけるHypoxiaが及ぼす影響の解析  

    第63回 歯科基礎医学会学術大会 

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    Event date： 2021.10

    Presentation type：Poster presentation  

  • 千葉紀香、大西智和、松口徹也   BMP-9⾻分化誘導シグナル伝達における転写因⼦Egr-1の重要な役割  

    第62回 歯科基礎医学会学術大会  歯科基礎医学会

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    Event date： 2020.9 - 2020.10

    Presentation type：Poster presentation  

  • 千葉紀香、林瑶大、佐藤大幹、成昌奐、大西智和、松口徹也   Hypoxiaが骨芽細胞分化に及ぼす影響の解析  

    第2回 南九州歯学会学術大会 

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    Event date： 2020.8

    Presentation type：Oral presentation (general)  

  • 千葉紀香, 大西智和, 松口徹也   Egr-1 plays an important role in BMP-9-induced osteoblast differentiation  

    第61回歯科基礎医学会学術大会  歯科基礎医学会

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    Event date： 2019.10

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Tomokazu Ohnishi, Tetsuya Matsuguchi   A distinct role of mast cells in Chlamydia pneumoniae lung infection  

    The 1st meeting of South Kyushu Dental Association 

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    Event date： 2019.6

    Language：Japanese   Presentation type：Poster presentation  

  • 千葉紀香, 楠山譲二, 大西智和, 松口徹也   クラミジア肺炎時の肺への免疫細胞の浸潤におけるマスト細胞の重要な役割  

    歯科基礎医学会学術大会 

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    Event date： 2018.9

    Language：Japanese   Presentation type：Poster presentation  

  • 松口 徹也, 千葉 紀香, 楠山 譲二, 大西 智和   BMP9の骨芽細胞分化誘導作用におけるPI3K-Akt-GSK3β/β-cateninシグナル経路の重要性  

    歯科基礎医学会学術大会 

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    Event date： 2018.9

    Language：Japanese   Presentation type：Poster presentation  

  • 大西 智和, 千葉 紀香, 松口 徹也, 久留 光博, 榮樂 菜保子, スバン・アミル   ケラチノサイトにおける紫外線B波長によるインターフェロンγ反応性の阻害はERストレスを介する  

    日本生化学会大会 

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    Event date： 2018.9

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Xiangrong Guan, Changfu Yao, Jonathan McQualter, Samriddha Ray, Barry R Stripp   Cytokines regulate progenitor cell expansion in lung parenchyma post H1N1 flu infection.   International conference

    Lung repair and regeneration consortium annual meeting 

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    Event date： 2016.9

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Changfu Yao, Xiangrong Guan, Samriddha Ray, Barry R Stripp   Immune-related signaling in club cells regulates progenitor cell expansion in lung parenchyma post H1N1 flu infection   International conference

    Lung repair and regeneration consortium annual meeting 

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    Event date： 2015.9

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Kenichi Shimada, Shuang Chen, Randa Alsabeh, Anatoly Slepenkin, Ellena Peterson, Timothy R Crother, Moshe Aiditi   Mast cells play an important role in Chlamydia pneumoniae lung infection by facilitating immune cell recruitment into the airway.   International conference

    LA immunology 

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    Event date： 2013.5

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Kenichi Shimada, Shuang Chen, Anatoly V Slepenkin, Ellena Peterson, Timothy R Crother, Moshe Arditi   Mast cells play an important role in Chlamydia pneumoniae-induced murine lung inflammation.   International conference

    Chlamydia basic research society sixth biennial meeting. 

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    Event date： 2013.3

    Language：English   Presentation type：Poster presentation  

  • Norika Chiba, Kenichi Shimada, Timothy R Crother, Shuang Chen, Randa Alsabeh, Moshe Arditi   Mast cells are required for proper immune responses against Chlamydia pneumoniae lung infection   International conference

    LA immunology 

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    Event date： 2012.5

    Language：English   Presentation type：Poster presentation  

  • Timothy R Crother, Jun Ma, Madhulika Jupelli, Norika Chiba, Randa Alsabeh, Kenichi Shimada, Moshe Arditi   Plasmacytoid dendritic cells orchestrate innate immune responses during Chlamydia pneumoniae infection in mice.   International conference

    LA immunology 

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    Event date： 2012.5

    Language：English   Presentation type：Oral presentation (general)  

  • Norika Chiba, Kenichi Shimada, Shuang Chen, Randa Alsabeh, Moshe Arditi   The role of mast cells during Chlamydia pneumoniae lung infection.   International conference

    Gordon Research Conference 

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    Event date： 2012.3

    Language：English   Presentation type：Poster presentation  

  • Timothy R Crother, Jun Ma, Kenichi Shimada, Randa Alsabeh, Norika Chiba, Moshe Arditi   Plasmacytoid dendritic cells are required to direct an effective Th1 response to Chlamydia pneumoniae infection in mice   International conference

    Gordon Research Conference 

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    Event date： 2010.3

    Language：English   Presentation type：Oral presentation (general)  

  • Norika Chiba, Akio Masuda, Yasunobu Yoshikai, Tetsuya Matsuguchi   Functional role of Cot/Tpl-2 mast cell responses to lipopolysaccharide and FceRI-clustering.  

    日本免疫学会総会 

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    Event date： 2008.12

    Language：Japanese   Presentation type：Oral presentation (general)  

  • Tomokuzu Ohnishi, Kenjiro Bandow, Kyoko Kakimoto, Norika Chiba, Tetsuya Matsuguchi   Effect of high glucose on mechanical stress-induced responses in osteoblast.  

    日本分子生物学会年会・日本生化学会大会 

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    Event date： 2008.12

    Language：Japanese   Presentation type：Poster presentation  

  • Kenjiro Bandow, Kyoko Kakimoto, Tomokuzu Ohnishi, Norika Chiba, Tetsuya Matsuguchi   Functional role of AMP-activated protein kinase (AMPK) in Chondrocytes.  

    日本分子生物学会年会・日本生化学会大会 

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    Event date： 2008.12

    Language：Japanese   Presentation type：Poster presentation  

  • Kenjiro Bandow, Tomokuzu Ohnishi, Kyoko Kakimoto, Norika Chiba, Tetsuya Matsuguchi   Effect of low intensity pulsed ultrasound (LIPUS) on transient receptor potential canonical (TPRC) expression in murine osteoblasts.  

    日本分子生物学会年会・日本生化学会大会 

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    Event date： 2007.12

    Language：Japanese   Presentation type：Poster presentation  

  • Kyoko Kakimoto, Norika Chiba, Kenjiro Bandow, Tomokuzu Ohnishi, Tetsuya Matsuguchi   Effect of Cot/Tpl-2 on IL-12/23/27 production by LPS-stimulated murine macrophages.  

    日本分子生物学会年会・日本生化学会大会 

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    Event date： 2007.12

    Language：Japanese   Presentation type：Poster presentation  

  • Tetsuya Matsuguchi, Norika Chiba, Kenjiro Bandow, Kyoko Kakimoto, Tomokuzu Ohnishi   The role of JNK during osteoblast differentiation.  

    日本分子生物学会年会・日本生化学会大会 

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    Event date： 2007.12

    Language：Japanese   Presentation type：Poster presentation  

  • Norika Chiba, Akio Masuda, Yasunobu Yoshikai, Tetsuya Matsuguchi   The role of Ceramide in LPS-induced cytokine production by mast cells.  

    日本免疫学会総会・学術集会  日本免疫学会

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    Event date： 2007.11

    Language：Japanese   Presentation type：Poster presentation  

  • 大西 智和, 成 昌奐, 千葉 紀香, 松口 徹也   All-transレチノイン酸はHes1を介して骨芽細胞のTnfrsf11b mRNA発現低下を誘導する  

    日本生化学会大会プログラム・講演要旨集  2020.9  (公社)日本生化学会

  • 千葉 紀香, 大西 智和, 松口 徹也   BMP-9による骨芽細胞分化におけるEgr-1の役割の解析  

    Journal of Oral Biosciences Supplement  2019.10  (一社)歯科基礎医学会

  • 千葉 紀香, 成 昌奐, 大西 智和, 松口 徹也   BMP-9骨分化誘導シグナル伝達における転写因子Egr-1の重要な役割  

    Journal of Oral Biosciences Supplement  2020.9  (一社)歯科基礎医学会

  • 榮樂 菜保子, 千葉 紀香, 大西 智和, 中村 利明, 松口 徹也, 野口 和行   BMP9のClass1 PI3K-Akt経路を介した直接的な骨芽細胞分化誘導  

    日本歯周病学会会誌  2019.10  (NPO)日本歯周病学会

  • 松口 徹也, 千葉 紀香, 楠山 譲二, 大西 智和   BMP9の骨芽細胞分化誘導作用におけるPI3K-Akt-GSK3β/β-cateninシグナル経路の重要性  

    Journal of Oral Biosciences Supplement  2018.9  (一社)歯科基礎医学会

  • 松口 徹也, 千葉 紀香, 成 昌奐, 大西 智和   BMP9刺激によって誘導されるHif-1αは解糖系酵素PDK1の発現を介して骨芽細胞分化に必須の役割を果たす  

    Journal of Oral Biosciences Supplement  2019.10  (一社)歯科基礎医学会

  • 成 昌奐, 大西 智和, 千葉 紀香, 松口 徹也   BMP9誘導性骨芽細胞分化におけるNotchエフェクター分子Hes1の発現機構および機能的意義の解明(Bone morphogenetic protein 9(BMP 9) induces the expression of Hes1 in osteoblasts: Analyses of its molecular mechanisms and functional roles)  

    Journal of Oral Biosciences Supplement  2020.9  (一社)歯科基礎医学会

  • 成 昌奐, 大西 智和, 千葉 紀香, 松口 徹也   Notchエフェクター分子Hes1のBMP9誘導性骨芽細胞分化における発現機構および機能的意義の解明(Elucidation of molecular mechanisms and functional roles of Notch signaling molecule Hes1 in BMP9-induced osteoblast differentiation)  

    Journal of Oral Biosciences Supplement  2019.10  (一社)歯科基礎医学会

  • 松口 徹也, 千葉 紀香, 成 昌奐, 大西 智和   低酸素誘導因子Hif-1α蛋白は骨芽細胞のBMP9刺激により早期に誘導され、解糖系酵素PDK1の発現を介して骨芽細胞分化に重要な役割を果たす  

    Journal of Oral Biosciences Supplement  2020.9  (一社)歯科基礎医学会

  • 大西 智和, 千葉 紀香, 松口 徹也   解糖阻害は初期分化段階の初代骨芽細胞においてユビキチン-プロテアソーム系を介してアポトーシスタンパク質の発現を増加させる  

    Journal of Oral Biosciences Supplement  2019.10  (一社)歯科基礎医学会

  • マルディヤントロ・フレディ , 成 昌奐, 千葉 紀香, 大西 智和, 松口 徹也   骨芽細胞分化における細胞内および分泌型オステオポンチンアイソフォームの異なる役割(Different roles of intracellular and secreted osteopontin isoforms in osteoblast differentiation)  

    Journal of Oral Biosciences Supplement  2022.9  (一社)歯科基礎医学会

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  • 千葉 紀香, 成 昌奐, 大西 智和, 松口 徹也   骨芽細胞分化におけるHypoxiaが及ぼす影響の解析(Hypoxia affects osteoblast differentiation)  

    Journal of Oral Biosciences Supplement  2021.10  (一社)歯科基礎医学会

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    Language：Japanese  

  • 大西 智和, 中村 利明, 嶋 香織, 野口 和行, 千葉 紀香, 松口 徹也   歯周炎によるSARS-CoV-2のプライミング因子であるTMPRSS2の歯肉発現増強(Periodontitis promotes gingival expression of TMPRSS2, a priming factor for SARS-CoV-2)  

    Journal of Oral Biosciences Supplement  2022.9  (一社)歯科基礎医学会

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  • 千葉 紀香, 成 昌奐, 大西 智和, 松口 徹也   EGR1はBMP9によるSMAD1/5活性化を増強して骨芽細胞分化を促進する(EGR1 plays an important role in BMP9-mediated osteoblast differentiation by promoting SMAD1/5 phosphorylation)  

    Journal of Oral Biosciences Supplement  2022.9  (一社)歯科基礎医学会

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    Language：Japanese  

  • 松口 徹也, 千葉 紀香, 大西 智和   BMP9はPI3K-Aktシグナル経路を介して骨芽細胞のHIF-1α蛋白発現を誘導する(BMP9 induces HIF-1A protein expression in osteoblasts through PI3K-Akt axis)  

    Journal of Oral Biosciences Supplement  2021.10  (一社)歯科基礎医学会

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  • 長澤 康行, 大西 智和, 三崎 太郎, 千葉 紀香, 山崎 博充, 庄嶋 健作, 新村 健, 松口 徹也   糖尿病性腎臓病とIgA腎症における尿中IgG分解産物の違い  

    日本腎臓学会誌  2025.6  (一社)日本腎臓学会

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  • 大西 智和, 橋本 雅仁, 千葉 紀香, 松口 徹也   糖尿病を発生したT.denticola感染を伴う実験的歯周炎マウスのIgA腎症の発症  

    Journal of Oral Biosciences Supplement  2024.11  (一社)歯科基礎医学会

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  • 千葉 紀香, 大西 智和, 松口 徹也   低酸素環境におけるマスト細胞でのLPS誘導性IL-13、IL-33発現におけるHIF-1αの役割  

    Journal of Oral Biosciences Supplement  2024.11  (一社)歯科基礎医学会

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    Language：Japanese  

  • 千葉 紀香, 大西 智和, 松口 徹也   マスト細胞の活性化に低酸素環境が及ぼす影響の解析  

    Journal of Oral Biosciences Supplement  2023.9  (一社)歯科基礎医学会

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  • 千葉 紀香, 大西 智和, 松口 徹也   マスト細胞における骨代謝関連遺伝子の発現に対するLPSの影響の解析  

    Journal of Oral Biosciences Supplement  2025.9  (一社)歯科基礎医学会

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Awards

  • 同窓会奨励賞

    2022.11   鹿児島大学歯学部同窓会   転写因子EGR1はBMP9によるSMAD1/5リン酸化を増強して骨芽細胞の分化を促進する

    千葉紀香

Research Projects

  • 慢性炎症性骨疾患における骨再生にマスト細胞が果たす役割とは？

    Grant number：26K12604  2026.4 - 2029.3

    日本学術振興会  科学研究費助成事業 

    千葉 紀香、松口 徹也、大西 智和

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    Authorship：Principal investigator  Grant type：Competitive

  • 糖尿病関連歯周炎による歯肉SARS-CoV-2感染関連因子の発現増強

    Grant number：23K09153  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    大西 智和, 千葉 紀香, 松口 徹也

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    高齢者及び基礎疾患をもつSARS-CoV-2感染者は重症化しやすく、オミクロン株においてもこの傾向は続いている。歯周炎患者はCOVID-19の罹患率が高いことが報告されており、我々はSARS-CoV-2感染関連因子の1つであるTransmembrane serine protease 2 (TMPRSS2)が歯周炎歯肉で上昇していることを報告した。従来のSARS-CoV-2デルタ株は、細胞に侵入する際にTMPRSS2がウィルス表面にあるスパイクタンパクを切断し、宿主の細胞表面にあるアンギオテンシン転換酵素２(ACE2)に結合する必要があった。しかし、オミクロン株ではウィルスのスパイクタンパクの構造が変化したため、TMPRSS2ではなくカテプシンBがスパイクタンパクを切断しCOVID-19の感染性を獲得することが明らかになった。そこで、本研究では２型糖尿病を伴う歯周炎においてCOVID-19の易感染性を示すため、歯肉にカテプシンＢの発現上昇を確認すると共にそのメカニズムを探った。まず、高脂肪食にて飼育することでマウスに２型糖尿病を発症させ、その後ワイヤー結紮にて実験的歯周炎を誘導した。その結果、２型糖尿病を伴う実験的歯周炎歯肉においてTMPRSS2の発現同様にカテプシンＢの発現を確認した。また、初代培養ケラチノサイトにおけるカテプシンＢの発現メカニズムを探るため、様々な炎症刺激においてカテプシンＢの発現の変化を検討した。その結果、IL-1, IL-6, TNF-αおよびLPSの刺激によってカテプシンＢの発現が上昇することが判明した。
    これらの結果は歯周炎による歯肉へのSARS-CoV-2の易感染性を示唆するものである。

  • Hypoxiaとなる炎症部位での骨nicheにおけるマスト細胞の役割とは何か？

    Grant number：23K09123  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    千葉 紀香, 松口 徹也, 大西 智和

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\3510000 （ Direct Cost: \2700000 、 Indirect Cost：\810000 ）

    本研究は、感染や骨折による炎症にて発生する低酸素環境においてマスト細胞の細胞応答性がどのように変化し、またそのことが骨形成・骨再生にどのように影響を与えるかを解明することをゴールとしている。マスト細胞は細菌由来成分に反応して各種サイトカインを分泌することが知られているが、低酸素下での反応についての詳細は今まで報告がない。そこで本年度は細菌性内毒素であるリポ多糖（LPS）に対するマスト細胞の免疫応答についてまずin vitroでの解析を主として行った。
    マスト細胞細胞株であるMC/9を酸素濃度2％（低酸素）の環境下にて培養したところ、低酸素誘導因子（HIF）の増加を確認した。次に、MC/9を酸素濃度それぞれ20％（大気）または2％にて一定時間静置した後にLPSの刺激を行い、誘導される細胞内シグナルとサイトカインの遺伝子発現を解析した。HIF1αの上昇は低酸素でのみ見られ、LPSの有無による有意な変化はなかった。また、細胞接着に関与する分子として知られる接着斑キナーゼ（FAK）のリン酸化が低酸素により促進されていることを確認した。興味深いことに、FAK阻害剤によってHIF1αの量が低下するが、HIF1αの阻害剤ではFAKのリン酸化は阻害されなかった。つまり、FAKのリン酸化はHIF１αよりも上流のイベントであることが分かる。これは報告のあるヒト臍帯血由来間葉系幹細胞とは異なる結果となった。LPSにより誘導されるサイトカインのうち、IL-６やTNF-αの炎症性サイトカインは酸素濃度により変化しないが、骨形成にも関わるIL-１３やIL-33の発現量は有意に増強されていた。また、この増強作用はFAK阻害剤、HIF1αノックダウンにより失われることも確認した。以上より、低酸素がマスト細胞内でFAKリン酸化を誘導、HIF1αを増加させ、サイトカイン特異的に産生を増強することが示された。

  • Identify a role of DUSP16 as a new therapeutic target of allergy

    Grant number：18K09508  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Chiba Norika

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    Our goal of this study is identifying a role of DUSP16, a MAPK phosphatase, in allergy as a therapeutic target. We analyzed allergic asthma animal model using DUSP16 knockout and wildtype mice. The number of infiltrate cells into bronchoalveolar lavage fluid (BALF) in asthmatic DUSP16 KO was relatively reduced in comparison with wild type. Also bone marrow-derived mast cells (BMMCs) were obtained from DUSP16 KO and wildtype. Both BMMCs were cultured in mast cell differentiation medium, and DUSP16 KO BMMCs showed slower growth than wildtype BMMCs. Also, DUSP16 gene expression in either antigen- or endotoxin-stimulated BMMCs was increased at early time point.
    Thus, DUSP16 may play an important role in mast cell proliferation and differentiation and DUSP16 would be a new therapeutic target for allergic asthma.

  • 骨代謝におけるマスト細胞の役割の解明

    2008.4 - 2009.3

    科学研究費補助金  若手研究(B)