| 久本 由香里（きゅうもと ゆかり） | データ更新日：2024.04.03 |
助教 ／
歯学研究院
歯学部門
口腔常態制御学
| 1. | Takashi Iezaki, Kazuya Fukasawa, Gyujin Park, Tetsuhiro Horie, Takashi Kanayama, Kakeru Ozaki, Yuki Onishi, Yoshifumi Takahata, Yukari Nakamura, Takeshi Takarada, Yukio Yoneda, Takashi Nakamura, Jean Vacher, Eiichi Hinoi, Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway., Molecular and cellular biology, 10.1128/MCB.01075-15, 36, 19, 2451-63, 2016.10, Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murine Ifrd1 increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion of Ifrd1 in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impaired in vitro in Ifrd1-deleted bone marrow macrophages (BMMs). Ifrd1 deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodeling in vivo and represents a therapeutic target for bone diseases.. |
| 2. | 顧 炯炎, 久本 由香里, 寺町 順平, 日浦 秀暢, 張 旌旗, 張 暁旭, 上原 範久, 山座 孝義, 久木田 明子, 久木田 敏夫, 破骨細胞機能制御に関連する新規破骨細胞特異的膜表面抗原, Journal of Oral Biosciences Supplement, 2020, 205-205, 2020.09. |
| 3. | Nobuya Hayashi, Yuki Inoue, Yukari Kyumoto, Toshio Kukita, Characteristics of differentiation of osteoclast cells irradiated with active species in atmospheric oxygen plasma, JAPANESE JOURNAL OF APPLIED PHYSICS, 10.35848/1347-4065/ab7ba9, 59, 2020.06, Variations in osteoclast cell number are observed when osteoclast precursor cells are irradiated with atmospheric dielectric barrier discharge plasma. Active species generated by the oxygen plasma control the differentiation function of the osteoclast precursor cells. Long-lifetime active species such as H2O2 and NOx- dissolved in the culture medium decrease the osteoclast number due to the inactivation of the differentiation function of the osteoclast precursor cells. When short-lifetime active species such as O* and OH* make contact with the osteoclast precursor cells directly, the osteoclast number tends to increase. Short-lifetime active species induce the enhancement of the gene expression of NFATc1. (C) 2020 The Japan Society of Applied Physics. |
| 4. | Mhd Fouad Zakaria, Soichiro Sonoda, Hiroki Kato, Lan Ma, Norihisa Uehara, Yukari Kyumoto-Nakamura, M Majd Sharifa, Liting Yu, Lisha Dai, Erika Yamauchi-Tomoda, Reona Aijima, Haruyoshi Yamaza, Fusanori Nishimura, Takayoshi Yamaza, Erythropoietin receptor signal is crucial for periodontal ligament stem cell-based tissue reconstruction in periodontal disease., Scientific reports, 10.1038/s41598-024-57361-y, 14, 1, 6719-6719, 14(1):6719, 2024.03, Alveolar bone loss caused by periodontal disease eventually leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are the tissue-specific cells for maintaining and repairing the periodontal ligament, cementum, and alveolar bone. Here, we investigated the role of erythropoietin receptor (EPOR), which regulates the microenvironment-modulating function of mesenchymal stem cells, in PDLSC-based periodontal therapy. We isolated PDLSCs from patients with chronic periodontal disease and healthy donors, referred to as PD-PDLSCs and Cont-PDLSCs, respectively. PD-PDLSCs exhibited reduced potency of periodontal tissue regeneration and lower expression of EPOR compared to Cont-PDLSCs. EPOR-silencing suppressed the potency of Cont-PDLSCs mimicking PD-PDLSCs, whereas EPO-mediated EPOR activation rejuvenated the reduced potency of PD-PDLSCs. Furthermore, we locally transplanted EPOR-silenced and EPOR-activated PDLSCs into the gingiva around the teeth of ligament-induced periodontitis model mice and demonstrated that EPOR in PDLSCs participated in the regeneration of the periodontal ligament, cementum, and alveolar bone in the ligated teeth. The EPOR-mediated paracrine function of PDLSCs maintains periodontal immune suppression and bone metabolic balance via osteoclasts and osteoblasts in the periodontitis model mice. Taken together, these results suggest that EPOR signaling is crucial for PDLSC-based periodontal regeneration and paves the way for the development of novel options for periodontal therapy.. |
| 5. | Norihisa Uehara, Yukari Kyumoto-Nakamura, Yoshikazu Mikami, Manabu Hayatsu, Soichiro Sonoda, Takayoshi Yamaza, Akiko Kukita, Toshio Kukita, miR-92a-3p encapsulated in bone metastatic mammary tumor cell–derived extracellular vesicles modulates mature osteoclast longevity, Cancer Science, 2022.12. |
| 6. | Jing-Qi Zhang, Akira Takahashi, Jiong-Yan Gu, Xiaoxu Zhang, Yukari Kyumoto-Nakamura, Akiko Kukita, Norihisa Uehara, Hidenobu Hiura, Takayoshi Yamaza, Toshio Kukita, In vitro and in vivo detection of tunneling nanotubes in normal and pathological osteoclastogenesis involving osteoclast fusion, Laboratory Investigation, 10.1038/s41374-021-00656-9, 101, 12, 1571-1584, 2021.12, Osteoclasts are multinucleated cells formed through specific recognition and fusion of mononuclear osteoclast precursors derived from hematopoietic stem cells. Detailed cellular events concerning cell fusion in osteoclast differentiation remain ambiguous. Tunneling nanotubes (TNTs), actin-based membrane structures, play an important role in intercellular communication between cells. We have previously reported the presence of TNTs in the fusion process of osteoclastogenesis. Here we analyzed morphological details of TNTs using scanning electron microscopy. The osteoclast precursor cell line RAW-D was stimulated to form osteoclast-like cells, and morphological details in the appearance of TNTs were extensively analyzed. Osteoclast-like cells could be classified into three types; early osteoclast precursors, late osteoclast precursors, and multinucleated osteoclast-like cells based on the morphological characteristics. TNTs were frequently observed among these three types of cells. TNTs could be classified into thin, medium, and thick TNTs based on the diameter and length. The shapes of TNTs were dynamically changed from thin to thick. Among them, medium TNTs were often observed between two remote cells, in which side branches attached to the culture substrates and beaded bulge-like structures were often observed. Cell-cell interaction through TNTs contributed to cell migration and rapid transport of information between cells. TNTs were shown to be involved in cell-cell fusion between osteoclast precursors and multinucleated osteoclast-like cells, in which movement of membrane vesicles and nuclei was observed. Formation of TNTs was also confirmed in primary cultures of osteoclasts. Furthermore, we have successfully detected TNTs formed between osteoclasts observed in the bone destruction sites of arthritic rats. Thus, formation of TNTs may be important for the differentiation of osteoclasts both in vitro and in vivo. TNTs could be one target cellular structure for the regulation of osteoclast differentiation and function in bone diseases.. |
| 7. | Toshio Kukita, Hidenobu Hiura, Jiong-Yan Gu, Jing-Qi Zhang, Yukari Kyumoto-Nakamura, Norihisa Uehara, Sara Murata, Soichiro Sonoda, Takayoshi Yamaza, Ichiro Takahashi, Akiko Kukita, Modulation of osteoclastogenesis through adrenomedullin receptors on osteoclast precursors: initiation of differentiation by asymmetric cell division, Laboratory Investigation, 10.1038/s41374-021-00633-2, 101, 11, 1449-1457, 2021.11, Adrenomedullin (ADM), a member of the calcitonin family of peptides, is a potent vasodilator and was shown to have the ability to modulate bone metabolism. We have previously found a unique cell surface antigen (Kat1 antigen) expressed in rat osteoclasts, which is involved in the functional regulation of the calcitonin receptor (CTR). Cross-linking of cell surface Kat1 antigen with anti-Kat1 antigen monoclonal antibody (mAbKat1) stimulated osteoclast formation only under conditions suppressed by calcitonin. Here, we found that ADM provoked a significant stimulation in osteoclastogenesis only in the presence of calcitonin; a similar biological effect was seen with mAbKat1 in the bone marrow culture system. This stimulatory effect on osteoclastogenesis mediated by ADM was abolished by the addition of mAbKat1. 125I-labeled rat ADM (125I-ADM)-binding experiments involving micro-autoradiographic studies demonstrated that mononuclear precursors of osteoclasts abundantly expressed ADM receptors, and the specific binding of 125I-ADM was markedly inhibited by the addition of mAbKat1, suggesting a close relationship between the Kat1 antigen and the functional ADM receptors expressed on cells in the osteoclast lineage. ADM receptors were also detected in the osteoclast progenitor cells in the late mitotic phase, in which only one daughter cell of the dividing cell express ADM receptors, suggesting the semiconservative cell division of the osteoclast progenitors in the initiation of osteoclastogenesis. Messenger RNAs for the receptor activity-modifying-protein 1 (RAMP1) and calcitonin receptor-like receptor (CRLR) were expressed in cells in the osteoclast lineage; however, the expression of RAMP2 or RAMP3 was not detected in these cells. It is suggested that the Kat1 antigen is involved in the functional ADM receptor distinct from the general ADM receptor, consisting of CRLR and RAMP2 or RAMP3. Modulation of osteoclastogenesis through functional ADM receptors abundantly expressed on mononuclear osteoclast precursors is supposed to be important in the fine regulation of osteoclast differentiation in a specific osteotrophic hormonal condition with a high level of calcitonin in blood.. |
| 8. | Soichiro Sonoda, Sara Murata, Hiroki Kato, Fouad Zakaria, Yukari Kyumoto-Nakamura, Norihisa Uehara, Haruyoshi Yamaza, Toshio Kukita, Takayoshi Yamaza, Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus, The Journal of Immunology, 10.4049/jimmunol.2001312, 206, 12, 3053-3063, 2021.06, Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)-like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV-administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.. |
| 9. | Soichiro Sonoda, Sara Murata, Kento Nishida, Hiroki Kato, Norihisa Uehara, Yukari N. Kyumoto, Haruyoshi Yamaza, Ichiro Takahashi, Toshio Kukita, Takayoshi Yamaza, Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model, Stem Cell Research & Therapy, 10.1186/s13287-020-01818-0, 11, 1, 296-296, 2020.12, Abstract Background Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) recovers bone loss in animal models of osteoporosis; however, the mechanisms underlying this remain unclear. Here, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) rescue osteoporotic phenotype. Methods EVs were isolated from culture supernatant of SHED. SHED-EVs were treated with or without ribonuclease and systemically administrated into ovariectomized mice, followed by the function of recipient bone marrow mesenchymal stem cells (BMMSCs) including telomerase activity, osteoblast differentiation, and sepmaphorine-3A (SEMA3A) secretion. Subsequently, human BMMSCs were stimulated by SHED-EVs with or without ribonuclease treatment, and then human BMMSCs were examined regarding the function of telomerase activity, osteoblast differentiation, and SEMA3A secretion. Furthermore, SHED-EV-treated human BMMSCs were subcutaneously transplanted into the dorsal skin of immunocompromised mice with hydroxyapatite tricalcium phosphate (HA/TCP) careers and analyzed the de novo bone-forming ability. Results We revealed that systemic SHED-EV-infusion recovered bone volume in ovariectomized mice and improved the function of recipient BMMSCs by rescuing the mRNA levels of Tert and telomerase activity, osteoblast differentiation, and SEMA3A secretion. Ribonuclease treatment depleted RNAs, including microRNAs, within SHED-EVs, and these RNA-depleted SHED-EVs attenuated SHED-EV-rescued function of recipient BMMSCs in the ovariectomized mice. These findings were supported by in vitro assays using human BMMSCs incubated with SHED-EVs. Conclusion Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating postmenopausal osteoporosis by targeting the telomerase activity of recipient BMMSCs.. |
| 10. | Yosuke Tanaka, Soichiro Sonoda, Haruyoshi Yamaza, Sara Murata, Kento Nishida, Yukari Kyumoto-Nakamura, Norihisa Uehara, Kazuaki Nonaka, Toshio Kukita, Takayoshi Yamaza, Acetylsalicylic Acid Treatment and Suppressive Regulation of AKT Accelerate Odontogenic Differentiation of Stem Cells from the Apical Papilla, Journal of Endodontics, 10.1016/j.joen.2019.01.016, 45, 5, 591-598.e6, 2019.05, [URL], Introduction: Stem cells isolated from the root apical papilla of human teeth (stem cells from the apical papilla [SCAPs])are capable of forming tooth root dentin and are a feasible source for bioengineered tooth root regeneration. In this study, we examined the effect of acetylsalicylic acid (ASA)on odontogenic differentiation of SCAPs in vitro and in vivo. Methods: SCAPs were cultured under odontogenic conditions supplemented with or without ASA. ASA-treated SCAPs were also subcutaneously transplanted into immunocompromised mice. Results: ASA accelerates in vitro and in vivo odontogenic differentiation of SCAPs associated with down-regulation of runt-related nuclear factor 2 and up-regulation of specificity protein 7, nuclear factor I C, and dentin phosphoprotein. ASA up-regulated the phosphorylation of AKT in the odontogenic SCAPs. Of interest, pretreatments with phosphoinositide 3-kinase inhibitor LY294402 and small interfering RNA for AKT promoted ASA-induced in vitro and in vivo odontogenic differentiation of SCAPs. LY294402 and small interfering RNA for AKT also suppressed the ASA-induced expression of runt-related nuclear factor 2 and enhanced ASA-induced expression of specificity protein 7, nuclear factor I C, and dentin phosphoprotein in SCAPs. Conclusions: These findings suggest that a combination of ASA treatment and suppressive regulation of the phosphoinositide 3-kinase–AKT signaling pathway is a novel approach for SCAP-based tooth root regeneration.. |
| 11. | Tamer Badawy, Yukari Kyumoto-Nakamura, Norihisa Uehara, Jingqi Zhang, Soichiro Sonoda, Hidenobu Hiura, Takayoshi Yamaza, Akiko Kukita, Toshio Kukita, Osteoblast lineage-specific cell-surface antigen (A7) regulates osteoclast recruitment and calcification during bone remodeling, Laboratory Investigation, 10.1038/s41374-018-0179-4, 99, 6, 866-884, 2019.01, [URL], Bone remodeling is a continuous process characterized by highly coordinated cell-cell interactions in distinct multi-cellular units. Osteoclasts, which are specialized bone resorbing cells, play a central role in bone remodeling. Although the RANKL/RANK axis determines the gross number of osteoclasts present in bone tissue, detailed molecular events regulating bone remodeling related to osteoclast recruitment, initiation of bone remodeling, and coupling of bone resorption and bone formation are still ambiguous. We hypothesized that osteoblast-specific cell-surface molecules contribute to the molecular modulation of bone remodeling. Therefore, we searched for regulatory cell-surface molecules expressed on osteoblasts by use of B-cell hybridoma technology. We obtained a monoclonal antibody A7 (A7 MAb) highly specific to cells of osteoblast-lineage. Here we describe the expression pattern and possible role of A7 antigen specifically recognized by A7 MAb. In vitro, A7 antigen was expressed on cell-surface of osteoblasts and osteoblast-like bone marrow stromal cells. In vivo, A7 antigen was detected in a subset of bone surface osteoblasts and in osteocytes, with a typical cell membrane expression pattern. Tissue array analysis showed only a limited expression of A7 antigen in osteocytes close to the bone surface. Immunoblotting and immunoprecipitation analysis showed that A7 antigen is a lineage-specific cell-surface protein with an approximate molecular weight of 45 KDa. Cross-linking of cell-surface A7 antigen in cultures of osteoclastogenesis showed stimulation of osteoclast formation. Marked suppression of calcification in primary osteoblast cultures was observed when A7 antigen was cross-linked with anti-A7 antigen MAb, A7 MAb. These data suggest that A7 antigen regulates recruitment of osteoclasts and triggering of calcification. A7 antigen may be an important molecule involved in the precise regulation of bone remodeling.. |
| 12. | Yosuke Tanaka, Soichiro Sonoda, Haruyoshi Yamaza, Sara Murata, Kento Nishida, Shion Hama, Yukari Kyumoto-Nakamura, Norihisa Uehara, Kazuaki Nonaka, Toshio Kukita, Takayoshi Yamaza, Suppression of AKT-mTOR signal pathway enhances osteogenic/dentinogenic capacity of stem cells from apical papilla, Stem Cell Research and Therapy, 10.1186/s13287-018-1077-9, 9, 1, 2018.11, [URL], Background: Stem cells from apical papilla (SCAP) are a subpopulation of mesenchymal stem cells (MSCs) isolated from the apical papilla of the developing tooth root apex of human teeth. Because of their osteogenic/dentinogenic capacity, SCAP are considered as a source for bone and dentin regeneration. However, little is understood about the molecular mechanism of osteogenic/dentinogenic differentiation of SCAP. Phosphoinositide 3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signal pathway participates in regulating the differentiation of various cell types, such as MSCs. In this study, we examined the role of the PI3K-AKT-mTOR signal pathway in the osteogenic/dentinogenic differentiation of SCAP. Moreover, we challenge to fabricate scaffold-free SCAP-based spheroidal calcified constructs. Methods: SCAP were pretreated with or without small interfering RNA for AKT (AKT siRNA), PI3K inhibitor LY294402, and mTOR inhibitor rapamycin and were cultured under osteogenic/dentinogenic differentiation to examine in vitro and in vivo calcified tissue formation. Moreover, SCAP-based cell aggregates were pretreated with or without LY294402 and rapamycin. The cell aggregates were cultured under osteogenic/dentinogenic condition and were analyzed the calcification of the aggregates. Results: Pretreatment with AKT siRNA, LY294402, and rapamycin enhances the in vitro and in vivo calcified tissue-forming capacity of SCAP. SCAP were fabricated as scaffold-free spheroids and were induced into forming calcified 3D constructs. The calcified density of the spheroidal constructs was enhanced when the spheroids were pretreated with LY294402 and rapamycin. Conclusions: Our findings indicate that the suppression of PI3K-AKT-mTOR signal pathway plays a role in not only enhancing the in vivo and in vitro osteogenic/dentinogenic differentiation of SCAP, but also promoting the calcification of scaffold-free SCAP-based calcified constructs. These findings suggest that a suppressive regulation of PI3K-AKT-mTOR signal pathway is a novel approach for SCAP-based bone and dentin regeneration.. |
| 13. | Tamer Badawy, Yukari Kyumoto-Nakamura, Norihisa Uehara, Jingqi Zhang, Hidenobu Hiura, Soichiro Sonoda, Takayoshi Yamaza, Akiko Kukita, Toshio Kukita, Unique Osteoblast-Specific Cell-Surface Antigen Useful for Odondoblast Ontology and Dentin Regeneration, International Journal of Oral Health & Dental Management, 10.33425/2639-9490.1018, 2, 2, 1-7, 2(1); 1-7., 2018.06. |
| 14. | Sonoda S., Mei Y. F., Atsuta I., Danjo A., Yamaza H., Hama S., Nishida K., Tang R., Kyumoto-Nakamura Y., Uehara N., Kukita T., Nishimura F., Yamaza T., Exogenous nitric oxide stimulates the odontogenic differentiation of rat dental pulp stem cells, SCIENTIFIC REPORTS, 10.1038/s41598-018-21183-6, 8, 1, 2018.02, Nitric oxide (NO) is thought to play a pivotal regulatory role in dental pulp tissues under both physiological and pathological conditions. However, little is known about the NO functions in dental pulp stem cells (DPSCs). We examined the direct actions of a spontaneous NO gas-releasing donor, NOC-18, on the odontogenic capacity of rat DPSCs (rDPSCs). In the presence of NOC-18, rDPSCs were transformed into odontoblast-like cells with long cytoplasmic processes and a polarized nucleus. NOC-18 treatment increased alkaline phosphatase activity and enhanced dentin-like mineralized tissue formation and the expression levels of several odontoblast-specific genes, such as runt related factor 2, dentin matrix protein 1 and dentin sialophosphoprotein, in rDPSCs. In contrast, carboxy-PTIO, a NO scavenger, completely suppressed the odontogenic capacity of rDPSCs. This NO-promoted odontogenic differentiation was activated by tumor necrosis factor-NF-κB axis in rDPSCs. Further in vivo study demonstrated that NOC-18-application in a tooth cavity accelerated tertiary dentin formation, which was associated with early nitrotyrosine expression in the dental pulp tissues beneath the cavity. Taken together, the present findings indicate that exogenous NO directly induces the odontogenic capacity of rDPSCs, suggesting that NO donors might offer a novel host DPSC-targeting alternative to current pulp capping agents in endodontics.. |
| 15. | Takuma Shiratori, Yukari Kyumoto-Nakamura, Akiko Kukita, Norihisa Uehara, Jingqi Zhang, Kinuko Koda, Mako Kamiya, Tamer Badawy, Erika Tomoda, Xianghe Xu, Takayoshi Yamaza, Yasuteru Urano, Kiyoshi Koyano and Toshio Kukita, IL-1β Induces Pathologically Activated Osteoclasts Bearing Extremely High Levels of Resorbing Activity: A Possible Pathological Subpopulation of Osteoclasts, Accompanied by Suppressed Expression of Kindlin-3 and Talin-1, The Journal of Immunology, 10.4049/jimmunol.1602035, 200, 1, 218-228, 2018.01. |
| 16. | Uehara N., Kukita A., Kyumoto-Nakamura Y., Yamaza T., Yasuda H., Kukita T., Osteoblast-derived Laminin-332 is a novel negative regulator of osteoclastogenesis in bone microenvironments, LABORATORY INVESTIGATION, 10.1038/labinvest.2017.55, 97, 10, 1235-1244, 2017.10, Laminin-332 (Lm-332), a major basement membrane protein, has been shown to provide a niche for some stem cells. Here, we found that Lm-332 was expressed in osteoblasts, and is implicated in the regulation of osteoclast differentiation. Immunofluorescence analysis of laminin-β3, a unique component of Lm-332, indicated specific expression of laminin-β3 in osteoblast-like cells localized on bone surface. RT-PCR analysis confirmed that α3, β3, and γ2 chains of Lm-332 were all expressed in primary osteoblasts prepared from mouse calvaria. Lm-332 markedly inhibited osteoclastogenesis induced by receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) when bone marrow-derived macrophages (BMMs) were cultured on Lm-332-coated plates. Lm-332 also blocked RANKL-induced activation of mitogen-activated protein kinases (MAPKs) (ERK, JNK, and p38) and expression of NFATc1, c-Fos, and c-Jun. Lm-332 suppressed osteoclast differentiation while retaining macrophage phenotypes, including nonspecific esterase activity and gene expression of lysozyme and EGF-like module-containing mucin-like hormone receptor-like 1 (Emr1). Furthermore, the treatment of primary osteoblasts with osteoclastogenic factors dramatically suppressed expression of Lm-332. These findings suggest that Lm-332 produced by osteoblasts in bone tissues has a pivotal role in controlling normal bone remodeling through suppressing osteoclastogenesis..  |
| 17. | Park G., Horie T., Kanayama T., Fukasawa K., Iezaki T., Onishi Y., Ozaki K., Nakamura Y., Yoneda Y., Takarada T., Hinoi E., The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes., 10.1111/febs.14019, 284, 5, 784-795, 2017.03. |
| 18. | Iezaki T., Fukasawa K., Park G., Horie T., Kanayama T., Ozaki K., Onishi Y., Takahata Y., Nakamura Y., Takarada T., Yoneda Y., Nakamura T., Vacher J., Hinoi E., Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway., 2016.09. |
| 19. | Li YJ., Kukita A., Kyumoto-Nakamura Y., Kukita T., Extremely High Expression of Antisense RNA for Wilms' Tumor 1 in Active Osteoclasts: Suppression of Wilms' Tumor 1 Protein Expression during Osteoclastogenesis., 10.1016/j.ajpath.2016.05.005, 186, 9, 2317-25, 2016.09. |
| 20. | Iezaki T., Onishi Y., Ozaki K., Fukasawa K., Takahata Y., Nakamura Y., Fujikawa K., Takarada T., Yoneda Y., Yamashita Y., Shioi G., Hinoi E., The Transcriptional Modulator Interferon-Related Developmental Regulator 1 in Osteoblasts Suppresses Bone Formation and Promotes Bone Resorption., 10.1002/jbmr.2720, 31, 3, 573-584, 2016.03. |
| 21. | Hinoi E., Nakamura Y., Takada S., Fujita H., Iezaki T., Hashizume S., Takahashi S., Odaka Y., Watanabe T., Yoneda Y., Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure., Diabetes, 10.2337/db13-0808, 63, 1, 162-175, 2014.01, Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet-induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1α signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes.. |
| 22. | Nakamura Y.*, Hinoi E.*, Iezaki T., Takada S., Hashizume S., Takahata Y., Tsuruta E., Takahashi S., Yoneda Y., Repression of adipogenesis through promotion of Wnt/ß-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia., BBA Mol. Basis Dis., 10.1016/j.bbadis.2013.03.010, 1832, 8, 1117-1128, 2013.08, Although tetradecanoyl phorbol acetate induced sequence-7 (TIS7) has been identified as a co-activator/repressor of gene transcription in different eukaryotic cells, little attention has been paid to the functionality of TIS7 in adipocytes. Here, we evaluated the possible role of TIS7 in mechanisms underlying the regulation of adipogenesis. TIS7 expression was preferentially up-regulated in white adipose tissues (WAT) of obesity model mice as well as in pre-adipocytic 3T3-L1 cells cultured under hypoxic conditions. TIS7 promoter activity was selectively enhanced by activating transcription factor-6 (ATF6) among different transcription factors tested, while induction of TIS7 by hypoxic stress was markedly prevented by knockdown of ATF6 by shRNA in 3T3-L1 cells. Overexpression of TIS7 markedly inhibited Oil Red O staining and expression of particular adipogenic genes in 3T3-L1 cells. TIS7 synergistically promoted gene transactivation mediated by Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin, while blockade of the Wnt/β-catenin pathway by a dominant negative form of T-cell factor-4 (DN-TCF4) markedly prevented the inhibition of adipogenesis in 3T3-L1 cells with TIS7 overexpression. TIS7 predominantly interacted with β-catenin in the nucleus of WAT in the genetically obese ob/ob mice as well as in 3T3-L1 cells cultured under hypoxic conditions. Both knockdown of TIS7 by shRNA and introduction of DN-TCF4 similarly reversed the hypoxia-induced inhibition of adipogenic gene expression in 3T3-L1 cells. These findings suggest that TIS7 could play a pivotal role in adipogenesis through interacting with β-catenin to promote the canonical Wnt signaling in pre-adipocytes under hypoxic stress such as obesity.. |
| 23. | Takarada T., Takarada-Iemata M., Takahata Y., Yamada D., Yamamoto T., Nakamura Y., Hinoi E., Yoneda Y., Osteoclastogenesis is negatively regulated by D-serine produced by osteoblasts., J. Cell. Physiol., 227, 3477-3487, 2012.10. |
| 24. | Takahata Y., Hinoi E., Takarada T., Nakamura Y., Ogawa S., Yoneda Y., Positive regulation by GABA(B) receptor subunit-1 of chondrogenesis through acceleration of nuclear translocation of activating transcription factor-4., J. Biol. Chem., 287, 33293-33303, 2012.09. |
| 25. | Uno K., Takarada T., Takarada-Iemata M., Nakamura Y., Fujita H., Hinoi E., Yoneda Y., Negative regulation of osteoblastogenesis through downregulation of runt-related transcription factor-2 in osteoblastic MC3T3-E1 cells with stable overexpression of the cystine/glutamate antiporter xCT subunit., J. Cell. Physiol., 226, 2953-2964, 2011.11. |
| 26. | Takahata Y., Takarada T., Hinoi E., Nakamura Y., Fujita H., Yoneda Y., Osteoblastic GABAB receptors negatively regulate osteoblastogenesis toward disturbance of osteoclastogenesis mediated by receptor activator of nuclear factor-kB ligand in mouse bone., J. Biol. Chem., 286, 32906-32917, 2011.09. |
| 27. | Takarada-Iemata M., Takarada T., Nakamura Y. Nakatani E., Hori O., Yoneda Y., Glutamate preferentially suppresses osteoblastogenesis than adipogenesis through the cystine/glutamate antiporter in mesenchymal stem cells., J. Cell. Physiol., 226, 652-665, 2011.03. |
| 28. | Nakamura Y.*, Hinoi E.*, Takarada T., Takahata Y., Yamamoto T., Fujita H., Takada S., Hashizume S., Yoneda Y., Positive regulation by GABABR1 subunit of leptin expression through gene transactivation in adipocytes., PLoS ONE., 6, e20167, 2011.03. |
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