研究者詳細 - 寳田　剛志

論文 - 寳田　剛志

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Induction and expansion of human PRRX1+ limb-bud-like mesenchymal cells from pluripotent stem cells. 国際誌

Daisuke Yamada, Masahiro Nakamura, Tomoka Takao, Shota Takihira, Aki Yoshida, Shunsuke Kawai, Akihiro Miura, Lu Ming, Hiroyuki Yoshitomi, Mai Gozu, Kumi Okamoto, Hironori Hojo, Naoyuki Kusaka, Ryosuke Iwai, Eiji Nakata, Toshifumi Ozaki, Junya Toguchida, Takeshi Takarada

Nature biomedical engineering 5 ( 8 ) 926 - 940 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Current protocols for the differentiation of human pluripotent stem cells (hPSCs) into chondrocytes do not allow for the expansion of intermediate progenitors so as to prospectively assess their chondrogenic potential. Here we report a protocol that leverages PRRX1-tdTomato reporter hPSCs for the selective induction of expandable and ontogenetically defined PRRX1+ limb-bud-like mesenchymal cells under defined xeno-free conditions, and the prospective assessment of the cells' chondrogenic potential via the cell-surface markers CD90, CD140B and CD82. The cells, which proliferated stably and exhibited the potential to undergo chondrogenic differentiation, formed hyaline cartilaginous-like tissue commensurate to their PRRX1-expression levels. Moreover, we show that limb-bud-like mesenchymal cells derived from patient-derived induced hPSCs can be used to identify therapeutic candidates for type II collagenopathy and we developed a method to generate uniformly sized hyaline cartilaginous-like particles by plating the cells on culture dishes coated with spots of a zwitterionic polymer. PRRX1+ limb-bud-like mesenchymal cells could facilitate the mass production of chondrocytes and cartilaginous tissues for applications in drug screening and tissue engineering.

DOI： 10.1038/s41551-021-00778-x

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悪性末梢神経鞘腫瘍におけるPRRX1の悪性化因子としての役割

たき平将太, 山田大祐, 高尾知佳, 中田英二, 近藤宏也, 佐藤浩平, 畑利彰, 藤原智洋, 国定俊之, 尾崎敏文, 宝田剛志

日本整形外科学会雑誌 95 ( 8 ) S1554 - S1554 2021年8月

Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. 国際誌

Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

International journal of cancer 149 ( 8 ) 1593 - 1604 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

DOI： 10.1002/ijc.33713

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RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. 国際誌

Filip Matthijssens, Nitesh D Sharma, Monique Nysus, Christian K Nickl, Huining Kang, Dominique R Perez, Beatrice Lintermans, Wouter Van Loocke, Juliette Roels, Sofie Peirs, Lisa Demoen, Tim Pieters, Lindy Reunes, Tim Lammens, Barbara De Moerloose, Filip Van Nieuwerburgh, Dieter L Deforce, Laurence C Cheung, Rishi S Kotecha, Martijn Dp Risseeuw, Serge Van Calenbergh, Takeshi Takarada, Yukio Yoneda, Frederik W van Delft, Richard B Lock, Seth D Merkley, Alexandre Chigaev, Larry A Sklar, Charles G Mullighan, Mignon L Loh, Stuart S Winter, Stephen P Hunger, Steven Goossens, Eliseo F Castillo, Wojciech Ornatowski, Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska

The Journal of clinical investigation 131 ( 6 ) 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.

DOI： 10.1172/JCI141566

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PRRX1 promotes malignant properties in human osteosarcoma. 国際誌

Ryoji Joko, Daisuke Yamada, Masahiro Nakamura, Aki Yoshida, Shota Takihira, Tomoka Takao, Ming Lu, Kohei Sato, Tatsuo Ito, Toshiyuki Kunisada, Eiji Nakata, Toshifumi Ozaki, Takeshi Takarada

Translational oncology 14 ( 1 ) 100960 - 100960 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Paired related homeobox 1 (PRRX1) is a marker of limb bud mesenchymal cells, and deficiency of p53 or Rb in Prrx1-positive cells induces osteosarcoma in several mouse models. However, the regulatory roles of PRRX1 in human osteosarcoma have not been defined. In this study, we performed PRRX1 immunostaining on 35 human osteosarcoma specimens to assess the correlation between PRRX1 level and overall survival. In patients with osteosarcoma, the expression level of PRRX1 positively correlated with poor prognosis or the ratio of lung metastasis. Additionally, we found PRRX1 expression on in 143B cells, a human osteosarcoma line with a high metastatic capacity. Downregulation of PRRX1 not only suppressed proliferation and invasion but also increased the sensitivity to cisplatin and doxorubicin. When 143B cells were subcutaneously transplanted into nude mice, PRRX1 knockdown decreased tumor sizes and rates of lung metastasis. Interestingly, forskolin, a chemical compound identified by Connectivity Map analysis using RNA expression signatures during PRRX1 knockdown, decreased tumor proliferation and cell migration to the same degree as PRRX1 knockdown. These results demonstrate that PRRX1 promotes tumor malignancy in human osteosarcoma.

DOI： 10.1016/j.tranon.2020.100960

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BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model. 国際誌

Akihiro Mikai, Mitsuaki Ono, Ikue Tosa, Ha Thi Thu Nguyen, Emilio Satoshi Hara, Shuji Nosho, Aya Kimura-Ono, Kumiko Nawachi, Takeshi Takarada, Takuo Kuboki, Toshitaka Oohashi

International journal of molecular sciences 21 ( 19 ) 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Medication-related osteonecrosis of the jaw (MRONJ) is a severe pathological condition associated mainly with the long-term administration of bone resorption inhibitors, which are known to induce suppression of osteoclast activity and bone remodeling. Bone Morphogenetic Protein (BMP)-2 is known to be a strong inducer of bone remodeling, by directly regulating osteoblast differentiation and osteoclast activity. This study aimed to evaluate the effects of BMP-2 adsorbed onto beta-tricalcium phosphate (β-TCP), which is an osteoinductive bioceramic material and allows space retention, on the prevention and treatment of MRONJ in mice. Tooth extraction was performed after 3 weeks of zoledronate (ZA) and cyclophosphamide (CY) administration. For prevention studies, BMP-2/β-TCP was transplanted immediately after tooth extraction, and the mice were administered ZA and CY for an additional 4 weeks. The results showed that while the tooth extraction socket was mainly filled with a sparse tissue in the control group, bone formation was observed at the apex of the tooth extraction socket and was filled with a dense connective tissue rich in cellular components in the BMP-2/β-TCP transplanted group. For treatment studies, BMP-2/β-TCP was transplanted 2 weeks after tooth extraction, and bone formation was followed up for the subsequent 4 weeks under ZA and CY suspension. The results showed that although the tooth extraction socket was mainly filled with soft tissue in the control group, transplantation of BMP-2/β-TCP could significantly accelerate bone formation, as shown by immunohistochemical analysis for osteopontin, and reduce the bone necrosis in tooth extraction sockets. These data suggest that the combination of BMP-2/β-TCP could become a suitable therapy for the management of MRONJ.

DOI： 10.3390/ijms21197028

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Core Binding Factors are essential for ovulation, luteinization, and female fertility in mice. 国際誌

Somang Lee-Thacker, Hayce Jeon, Yohan Choi, Ichiro Taniuchi, Takeshi Takarada, Yukio Yoneda, CheMyong Ko, Misung Jo

Scientific reports 10 ( 1 ) 9921 - 9921 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Core Binding Factors (CBFs) are a small group of heterodimeric transcription factor complexes composed of DNA binding proteins, RUNXs, and a non-DNA binding protein, CBFB. The LH surge increases the expression of Runx1 and Runx2 in ovulatory follicles, while Cbfb is constitutively expressed. To investigate the physiological significance of CBFs, we generated a conditional mutant mouse model in which granulosa cell expression of Runx2 and Cbfb was deleted by the Esr2Cre. Female Cbfbflox/flox;Esr2cre/+;Runx2flox/flox mice were infertile; follicles developed to the preovulatory follicle stage but failed to ovulate. RNA-seq analysis of mutant mouse ovaries collected at 11 h post-hCG unveiled numerous CBFs-downstream genes that are associated with inflammation, matrix remodeling, wnt signaling, and steroid metabolism. Mutant mice also failed to develop corpora lutea, as evident by the lack of luteal marker gene expression, marked reduction of vascularization, and excessive apoptotic staining in unruptured poorly luteinized follicles, consistent with dramatic reduction of progesterone by 24 h after hCG administration. The present study provides in vivo evidence that CBFs act as essential transcriptional regulators of both ovulation and luteinization by regulating the expression of key genes that are involved in inflammation, matrix remodeling, cell differentiation, vascularization, and steroid metabolisms in mice.

DOI： 10.1038/s41598-020-64257-0

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Establishment of a tTA-dependent photoactivatable Cre recombinase knock-in mouse model for optogenetic genome engineering. 査読国際誌

Tomoka Takao, Yuichi Hiraoka, Kenji Kawabe, Daisuke Yamada, Lu Ming, Kohichi Tanaka, Moritoshi Sato, Takeshi Takarada

Biochemical and biophysical research communications 526 ( 1 ) 213 - 217 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The Cre-loxP recombination system is widely used to generate genetically modified mice for biomedical research. Recently, a highly efficient photoactivatable Cre (PA-Cre) based on reassembly of split Cre fragments has been established. This technology enables efficient DNA recombination that is activated upon blue light illumination with spatiotemporal precision. In this study, we generated a tTA-dependent photoactivatable Cre-loxP recombinase knock-in mouse model (TRE-PA-Cre mice) using a CRISPR/Cas9 system. These mice were crossed with ROSA26-tdTomato mice (Cre reporter mouse) to visualize DNA recombination as marked by tdTomato expression. We demonstrated that external noninvasive LED blue light illumination allows efficient DNA recombination in the liver of TRE-PA-Cre:ROSA26-tdTomato mice transfected with tTA expression vectors using hydrodynamic tail vein injection. The TRE-PA-Cre mouse established here promises to be useful for optogenetic genome engineering in a noninvasive, spatiotemporal, and cell-type specific manner in vivo.

DOI： 10.1016/j.bbrc.2020.03.015

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A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. 国際誌

Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Xianpeng Ge, Ren Xu, Na Li, Minkyung Song, Hyunho Chun, Seoyeon Bok, Julia F Charles, Odile Filhol-Cochet, Brigitte Boldyreff, Teresa Dinter, Paul B Yu, Ning Kon, Wei Gu, Takeshi Takarada, Matthew B Greenblatt, Jae-Hyuck Shim

Nature communications 11 ( 1 ) 2289 - 2289 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.

DOI： 10.1038/s41467-020-16038-6

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骨肉腫におけるPRRX1の発現は悪性化に関与する

上甲良二, 山田大祐, 中田英二, たき平将太, 尾崎敏文, 宝田剛志

中部日本整形外科災害外科学会雑誌 63 ( 春季学会 ) 212 - 212 2020年4月

Glutamatergic neurons in the medial prefrontal cortex mediate the formation and retrieval of cocaine-associated memories in mice. 査読国際誌

Tong Zhang, Junko Yanagida, Hironori Kamii, Shintaro Wada, Masaki Domoto, Hitoki Sasase, Satoshi Deyama, Takeshi Takarada, Eiichi Hinoi, Kenji Sakimura, Akihiro Yamanaka, Takashi Maejima, Michihiro Mieda, Takeshi Sakurai, Naoya Nishitani, Kazuki Nagayasu, Shuji Kaneko, Masabumi Minami, Katsuyuki Kaneda

Addiction biology 25 ( 1 ) e12723 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

In drug addiction, environmental stimuli previously associated with cocaine use readily elicit cocaine-associated memories, which persist long after abstinence and trigger cocaine craving and consumption. Although previous studies suggest that the medial prefrontal cortex (mPFC) is involved in the expression of cocaine-addictive behaviors, it remains unclear whether excitatory and inhibitory neurons in the mPFC are causally related to the formation and retrieval of cocaine-associated memories. To address this issue, we used the designer receptors exclusively activated by designer drugs (DREADD) technology combined with a cocaine-induced conditioned place preference (CPP) paradigm. We suppressed mPFC neuronal activity in a cell-type- and timing-dependent manner. C57BL/6J wild-type mice received bilateral intra-mPFC infusion of an adeno-associated virus (AAV) expressing inhibitory DREADD (hM4Di) under the control of CaMKII promotor to selectively suppress mPFC pyramidal neurons. GAD67-Cre mice received bilateral intra-mPFC infusion of a Cre-dependent AAV expressing hM4Di to specifically silence GABAergic neurons. Chemogenetic suppression of mPFC pyramidal neurons significantly attenuated both the acquisition and expression of cocaine CPP, while suppression of mPFC GABAergic neurons affected neither the acquisition nor expression of cocaine CPP. Moreover, chemogenetic inhibition of mPFC glutamatergic neurons did not affect the acquisition and expression of lithium chloride-induced conditioned place aversion. These results suggest that the activation of glutamatergic, but not GABAergic, neurons in the mPFC mediates both the formation and retrieval of cocaine-associated memories.

DOI： 10.1111/adb.12723

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【脳の半分を占めるグリア細胞脳と心と体をつなぐ"膠"】(第2章)グリア細胞と神経免疫・臓器連関ペリサイト機能欠損による血液脳関門の破綻

中里亮太, 山田大祐, 宝田剛志

実験医学 37 ( 17 ) 2854 - 2860 2019年11月

記述言語：日本語出版者・発行元：(株)羊土社

ペリサイト(周皮細胞)は、血管を構成する血管内皮細胞の周囲に接着し、血管の安定化や機能維持において重要な役割を担う。特に、中枢神経系においては、血液脳関門の形成・維持においてペリサイトの存在が不可欠であることが知られている。正常な神経機能を維持するうえで、血液脳関門は必須な保護機構であり、加齢などに伴う血液脳関門の機能低下はさまざまな神経変性疾患を引き起こす原因の1つであると考えられている。これらの理由から、近年、ペリサイトによる血液脳関門の機能維持メカニズムは大きな注目を集めている。(著者抄録)

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Postnatal Runx2 deletion leads to low bone mass and adipocyte accumulation in mice bone tissues. 査読国際誌

Ikue Tosa, Daisuke Yamada, Misa Yasumatsu, Eiichi Hinoi, Mitsuaki Ono, Toshitaka Oohashi, Takuo Kuboki, Takeshi Takarada

Biochemical and biophysical research communications 516 ( 4 ) 1229 - 1233 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Global gene deletion studies have established that Runt-related transcription factor-2 (Runx2) is essential during skeletogenesis for osteoblastic differentiation in both intramembranous and endochondral ossification processes. However, the postnatal significance of Runx2 in vivo is poorly understood because a global Runx2 deletion causes perinatal lethality. In this study, we generated tamoxifen-induced Runx2 global deficient mice by crossing Runx2flox mice with ROSA26-CreERT2 mice (Rosa26-CreERT2; Runx2flox/flox). Four-week-old mice were intraperitoneally treated with tamoxifen for five consecutive days, sacrificed, and analyzed six weeks after tamoxifen administration. Deletion of Runx2 led to low bone mass, which is associated with decreased bone formation and bone resorption as well as excessive bone marrow adiposity. Collectively, postnatal Runx2 absolutely plays an important role in maintaining the homeostasis of bone tissues not only in bone mass, but also in the bone marrow environment.

DOI： 10.1016/j.bbrc.2019.07.014

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時期特異的Runx2欠損マウスを用いた成体におけるRunx2の機能解析

土佐郁恵, 河邊憲司, 大野充昭, 窪木拓男, 宝田剛志

日本骨代謝学会学術集会プログラム抄録集 37回 216 - 216 2019年9月

Runx2 is required for postnatal intervertebral disc tissue growth and development. 査読国際誌

Lifan Liao, Hua Jiang, Yunshan Fan, Ronald S Lu, Changli Wei, Takeshi Takarada, Shisheng He, Di Chen

Journal of cellular physiology 234 ( 5 ) 6679 - 6687 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Runx2 plays an essential role in embryonic disc tissue development in mice. However, the role of runt-related transcription factor 2 (Runx2) in postnatal disc tissue growth and development has not been defined. In the present studies, we generated Runx2 conditional knockout (KO) mice (Runx2Agc1ER ), in which Runx2 was deleted in Aggrecan-expressing cells in disc tissue at postnatal 2-weeks of age. We then analyzed changes in disc tissue growth and development using histology and immunohistochemical methods in 3-month-old mice. We found that large vacuolated notochordal cells were accumulated in the nucleus pulposus (NP) in Runx2 KO mice. The growth plate cartilage tissue in the disc was thicker in Runx2 KO mice. We also found a significant upregulation of Indian hedgehog (Ihh) expression in the cells in NP cells and in annulus fibrosus cells of Runx2 KO mice. These results demonstrated that Runx2 may play an important role in postnatal disc tissue development through interacting with Ihh signaling.

DOI： 10.1002/jcp.27410

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骨髄間葉系幹細胞におけるRunx2の発現低下は骨および骨髄の加齢様変化をもたらす

土佐郁恵, 山田大祐, 大野充昭, 大橋俊孝, 窪木拓男, 宝田剛志

日本補綴歯科学会誌 11 ( 特別号 ) 129 - 129 2019年5月

Glutamatergic neurons in the medial prefrontal cortex mediate the formation and retrieval of cocaine-associated memories in mice

Zhang, Tong, Yanagida, Junko, Kamii, Hironori, Wada, Shintaro, Domoto, Masaki, Sasase, Hitoki, Deyama, Satoshi, Takarada, Takeshi, Hinoi, Eiichi, Sakimura, Kenji, Yamanaka, Akihiro, Maejima, Takashi, Mieda, Michihiro, Sakurai, Takeshi, Nishitani, Naoya, Nagayasu, Kazuki, Kaneko, Shuji, Minami, Masabumi, Kaneda, Katsuyuki

Addiction biology Epub 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/adb.12723

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Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment. 査読国際誌

Ha Thi Nguyen, Mitsuaki Ono, Yasutaka Oida, Emilio Satoshi Hara, Taishi Komori, Kentaro Akiyama, Ha Thi Thu Nguyen, Kyaw Thu Aung, Hai Thanh Pham, Ikue Tosa, Takeshi Takarada, Koichi Matsuo, Toshihide Mizoguchi, Toshitaka Oohashi, Takuo Kuboki

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 ( 2 ) 327 - 332 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone morphogenetic protein 2 (BMP-2) is widely known as a potent growth factor that promotes bone formation. However, an increasing number of studies have demonstrated side effects of BMP-2 therapy. A deeper understanding of the effect of BMP-2 on cells other than those involved directly in bone remodeling is of fundamental importance to promote a more effective delivery of BMP-2 to patients. In this study, we aimed to investigate the effect of BMP-2 in the marrow environment. First, BMP-2 adsorbed onto titanium implants was delivered at the tooth extraction socket (marrow-absent site) or in the mandible marrow of beagle dogs. BMP-2 could induce marked bone formation around the implant at the tooth extraction socket. Surprisingly, however, no bone formation was observed in the BMP-2-coated titanium implants inserted in the mandible marrow. In C57BL/6 mice, BMP-2 adsorbed in freeze-dried collagen pellets could induce bone formation in marrow-absent calvarial bone. However, similar to the canine model, BMP-2 could not induce bone formation in the femur marrow. Analysis of osteoblast differentiation using Col1a1(2.3)-GFP transgenic mice revealed a scarce number of osteoblasts in BMP-2-treated femurs, whereas in the control group, osteoblasts were abundant. Ablation of femur marrow recovered the BMP-2 ability to induce bone formation. In vitro experiments analyzing luciferase activity of C2C12 cells with the BMP-responsive element and alkaline phosphatase activity of MC3T3-E1 osteoblasts further revealed that bone marrow cells inhibit the BMP-2 effect on osteoblasts by direct cell-cell contact. Collectively, these results showed that the effect of BMP-2 in inducing bone formation is remarkably repressed by marrow cells via direct cell-cell contact with osteoblasts; this opens new perspectives on the clarification of the side-effects associated with BMP-2 application. © 2018 American Society for Bone and Mineral Research.

DOI： 10.1002/jbmr.3598

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Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging. 査読国際誌

Effendi N, Mishiro K, Takarada T, Yamada D, Nishii R, Shiba K, Kinuya S, Odani A, Ogawa K

Bioorganic & medicinal chemistry 27 ( 2 ) 383 - 393 2019年1月

Molecular understanding of hierarchy and lineage of mesenchymal stem cells in vivo 査読

Kawabe, K., Takarada, T.

Folia Pharmacologica Japonica 153 ( 2 ) 67 - 72 2019年

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