Mechanisms of pathological bone formation and potential applications

• Project/Area Number: 17H04317
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Saitama Medical University
• Principal Investigator: KATAGIRI TAKENOBU 埼玉医科大学, 医学部, 教授 (80245802)
• Co-Investigator(Kenkyū-buntansha): 自見 英治郎 九州大学, 歯学研究院, 教授 (40276598) ; 仲地 ゆたか 熊本大学, 大学院生命科学研究部(医), 助教 (10522097)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 骨形成 / 石灰化 / BMP / Wnt / 異所性骨化 / 筋組織 / 骨組織 / シグナル伝達 / 骨格筋 / 再生医学 / 分化 / 前駆細胞

Outline of Final Research Achievements

We examined molecular mechanisms of bone formation especially in pathological conditions using genetically engineered mice and cultured cels. We found a novel axis of transcriptional coactivator Smad4 - growth factor Wnt7b as an important pathway on bone formation in vivo. In addition, we examined a murine in vivo model of trauma-induced hard tissue formation in skeletal muscle tissue. This event was different from bone formation and was precipitation of apatite crystals.

Academic Significance and Societal Importance of the Research Achievements

本研究で明らかとなった転写共役因子Smad4を介したWnt7bの発現制御による骨形成の調節機構は、新しい骨形成制御機構である。この骨形成調節機構を人為的に制御できる生理活性物質は、新しい骨形成制御分子として、骨粗鬆症などの疾患い応用できる可能性がある。また、本制御系の異常が、発症原因が不明の骨関連疾患の一因となる可能性も示唆される。筋組織における外傷性の硬組織形成モデルの解析から、形成された組織は骨や軟骨ではなく、リンとカルシウムの結晶析出であることが判明した。従って、予防や治療を考える上で、骨形成は異なるアプローチが必要であることが明らかとなった。

Research Products

• [Journal Article] Functional characterization of a unique mutant of ALK2, p.K400E, that is associated with a skeletal disorder, diffuse idiopathic skeletal hyperostosis (2020)
  • Author(s): Tsukamoto Sho、Kuratani Mai、Katagiri Takenobu
  • Journal Title: Bone Volume: 137 Pages: 115410-115410
  • DOI: 10.1016/j.bone.2020.115410
  • Peer Reviewed
• [Journal Article] Fibrodysplasia ossificans progressiva: Review and research activities in Japan (2020)
  • Author(s): Haga Nobuhiko、Nakashima Yasuharu、Kitoh Hiroshi、Kamizono Junji、Katagiri Takenobu、Saijo Hideto、Tsukamoto Sho、Shinoda Yusuke、Sawada Ryoko、Nakahara Yasuo
  • Journal Title: Pediatrics International Volume: 62 Issue: 1 Pages: 3-13
  • DOI: 10.1111/ped.14065
  • Peer Reviewed / Open Access
• [Journal Article] Dual usage of a stage-specific fluorescent reporter system based on a helper-dependent adenoviral vector to visualize osteogenic differentiation (2019)
  • Author(s): Sone Takefumi、Shin Masashi、Ouchi Takehito、Sasanuma Hiroki、Miyamoto Arei、Ohte Satoshi、Tsukamoto Sho、Nakanishi Mahito、Okano Hideyuki、Katagiri Takenobu、Mitani Kohnosuke
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 9705-9705
  • DOI: 10.1038/s41598-019-46105-y
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of Heterotopic Bone-Inducing Activity in Hard Tissues and the TGF-β Superfamily (2018)
  • Author(s): Katagiri Takenobu、Tsukamoto Sho、Nakachi Yutaka、Kuratani Mai
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 11 Pages: 3586-3586
  • DOI: 10.3390/ijms19113586
  • Peer Reviewed / Open Access
• [Journal Article] Recent Topics in Fibrodysplasia Ossificans Progressiva (2018)
  • Author(s): Katagiri Takenobu、Tsukamoto Sho、Nakachi Yutaka、Kuratani Mai
  • Journal Title: Endocrinology and Metabolism Volume: 33 Issue: 3 Pages: 331-331
  • DOI: 10.3803/enm.2018.33.3.331
  • Peer Reviewed / Open Access
• [Journal Article] A potential novel option for cancer immunotherapy - TLR7 stimulation inhibits malignant melanoma bone invasion (2018)
  • Author(s): Katagiri Takenobu
  • Journal Title: Oncotarget Volume: 9 Issue: 61 Pages: 31792-3179
  • DOI: 10.18632/oncotarget.25872
  • Peer Reviewed
• [Journal Article] BMPR2 inhibits activin and BMP signaling via wild-type ALK2 (2018)
  • Author(s): Olsen Oddrun Elise、Sankar Meenu、Elsaadi Samah、Hella Hanne、Buene Glenn、Darvekar Sagar Ramesh、Misund Kristine、Katagiri Takenobu、Knaus Petra、Holien Toril
  • Journal Title: Journal of Cell Science Volume: 131 Issue: 11 Pages: 213512-213512
  • DOI: 10.1242/jcs.213512
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders (2018)
  • Author(s): Machiya Aiko、Tsukamoto Sho、Ohte Satoshi、Kuratani Mai、Fujimoto Mai、Kumagai Keigo、Osawa Kenji、Suda Naoto、Bullock Alex N.、Katagiri Takenobu
  • Journal Title: Bone Volume: 111 Pages: 101-108
  • DOI: 10.1016/j.bone.2018.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva (2018)
  • Author(s): Katagiri Takenobu、Tsukamoto Sho、Kuratani Mai
  • Journal Title: Bone Volume: 109 Pages: 241-250
  • DOI: 10.1016/j.bone.2017.07.024
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms for activation of mutant Activin receptor-like kinase 2 in fibrodysplasia ossificans progressiva. (2017)
  • Author(s): Fujimoto M, Suda N, and Katagiri T
  • Journal Title: Journal of Oral Biosciences Volume: 59 Pages: 121-126
  • Peer Reviewed / Open Access
• [Journal Article] Scopranones with Two Atypical Scooplike Moieties Produced by Streptomyces sp. BYK-11038 (2017)
  • Author(s): Uchida Ryuji、Lee Daiki、Suwa Ibuki、Ohtawa Masaki、Watanabe Nozomu、Demachi Ayumu、Ohte Satoshi、Katagiri Takenobu、Nagamitsu Tohru、Tomoda Hiroshi
  • Journal Title: Organic Letters Volume: 19 Issue: 21 Pages: 5980-5983
  • DOI: 10.1021/acs.orglett.7b03003
  • Peer Reviewed / Open Access
• [Presentation] A novel molecular mechanism for the activation of a BMP type I receptor, ALK2, proposed from research on fibrodysplasia ossificans progressiva (2020)
  • Author(s): Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Takaishi K, Kunikata T, Nakamura K, Kawaguchi Y
  • Organizer: Gordon Research Conference on Bones and Teeth
  • Int'l Joint Research / Invited
• [Presentation] 進行性骨化性線維異形成症に対する治療薬の開発研究 (2019)
  • Author(s): 片桐岳信
  • Organizer: 脊柱靭帯骨化症に関する調査研究 令和元年度 第2回班会議
  • Invited
• [Presentation] 進行性骨化性線維異形成症（FOP)に対する抗ALK２抗体の開発 (2019)
  • Author(s): 片桐岳信
  • Organizer: 精神・神経疾患研究開発費 ジストロフィン欠損モデル動物を基盤とした筋ジストロフィーの新しい治療法開発 令和元年度 研究班会議
  • Invited
• [Presentation] Characterization of an anti-ALK2 blocking antibody, DaVinci (2019)
  • Author(s): Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Takaishi K, Kunikata T, Nakamura K, Kawaguchi Y
  • Organizer: 2019 FOP Family Gathering
  • Int'l Joint Research / Invited
• [Presentation] Characterization of an anti-ALK2 blocking antibody, DaVinci. (2019)
  • Author(s): Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Takaishi K, Kunikata T, Nakamura K, Kawaguchi Y
  • Organizer: 2019 FOP Drug Development Forum
  • Int'l Joint Research / Invited
• [Presentation] 病態生理部門における骨を核とした研究活動 (2019)
  • Author(s): 片桐岳信
  • Organizer: 第17回RCGMフロンティアシンポジウム
  • Invited
• [Presentation] 抗ALK2阻害抗体の結合と阻害活性に重要なALK2細胞外領域アミノ酸残基の同定 (2019)
  • Author(s): 片桐岳信、塚本翔、倉谷麻衣
  • Organizer: 第37回日本骨代謝学会学術集会
• [Presentation] Identiffication of a critical amino acid residue in ALK2 for the binding and inhibition by the anti-ALK2 blocking antibody (2019)
  • Author(s): Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Takaishi K, Kunikata T, Nakamura K, Kawaguchi Y, Hasegawa J
  • Organizer: ASBMR 2019 Annual meeting
  • Int'l Joint Research
• [Presentation] Wnt7b expressed by hypertrophic chondrocytes is a critical inducer of bone formation during endochondral ossification (2019)
  • Author(s): Tsukamoto S, Kuratani M, Sekine N, Okubo M, Tanaka S, Jimi E, Oda H, Katagiri T
  • Organizer: ASBMR 2019 Annual meeting
• [Presentation] Wnt7bは内軟性国家における骨形成誘導因子である (2019)
  • Author(s): 塚本翔、倉谷麻衣、関根典子、大久保美里、田中伸哉、自見英治郎、織田弘美、片桐岳信
  • Organizer: 第17回RCGMフロンティアシンポジウム
• [Presentation] A crosstalk between Wnt and TGF-β/BMP families regulates endochondral bone formation (2019)
  • Author(s): Tsukamoto S, Kuratani M, Sekine N, Okubo M, Tanaka S, Jimi E, Oda H, Katagiri T
  • Organizer: Gordon Research Conference on Wnt Signaling
  • Int'l Joint Research
• [Presentation] Identiffication of a critical amino acid residue in ALK2 for the binding and inhibition by the anti-ALK2 blocking antibody (2019)
  • Author(s): Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Takaishi K, Kunikata T, Nakamura K, Kawaguchi Y, Hasegawa J
  • Organizer: FASEB SRC on TGF-β Superfamily
  • Int'l Joint Research
• [Presentation] A role of dimer formation of ALK2, a BMP typeⅠ receptor in the activation of intracellular signaling (2019)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Kuratani M, Ohte S, Sekine N, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y, Hasegawa J
  • Organizer: Gordon Research Conference on Cartilage
  • Int'l Joint Research
• [Presentation] 内軟骨性骨化におけるBMPとWntの新たなクロストーク (2019)
  • Author(s): 塚本翔、倉谷麻衣、関根典子、大久保美里、田中伸哉、自見英治郎、織田弘美、片桐岳信
  • Organizer: 第５回日本骨免疫学会
• [Presentation] Development of blocking antibodies against ALK2 for fibrodysplasia ossificans progressiva. (2018)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Kuratani M, Ohte S, Sekine N, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y
  • Organizer: Muscle 2018
  • Int'l Joint Research
• [Presentation] BMP受容体ALK2に対する特異的阻害抗体の解析. (2018)
  • Author(s): 片桐岳信、辻真之介、塚本翔、倉谷麻衣、大手聡、高石巨澄、中村健介、川口喜朗、長谷川淳
  • Organizer: 第4回日本骨免疫学会
• [Presentation] 異所性骨化の発症機序の解明と治療薬開発への応用. (2018)
  • Author(s): 片桐岳信
  • Organizer: 第39回日本再生・医学会
  • Invited
• [Presentation] A novel crosstalk between the TGF-β and Wnt families in endochondral ossification. (2018)
  • Author(s): Tsukamoto, S., Kuratani, M., Sekine, N., Okubo, M., Nakachi, Y., Katagiri, T
  • Organizer: The 16th RCGM International Symposium of Academic Frontier
  • Int'l Joint Research
• [Presentation] Gene analysis related to Gender Dysphoria. (2018)
  • Author(s): Nakachi, Y., Tsukamoto, S., Iwanaga, Y., Katagiri, T
  • Organizer: The 16th RCGM International Symposium of Academic Frontier
  • Int'l Joint Research
• [Presentation] A novel crosstalk between TGF-β/BMP and Wnt families through Smad4 in endochondral ossification. (2018)
  • Author(s): Tsukamoto, S., Kuratani, M., Sekine, N., Okubo, M., Nakachi, Y., Tanaka, S., Jimi, E., Oda, H., Katagiri, T.
  • Organizer: ASBMR 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] A novel crosstalk between TGF-β/BMP and Wnt families through Smad4 in endochondral ossification. (2018)
  • Author(s): Tsukamoto, S., Kuratani, M., Sekine, N., Okubo, M., Nakachi, Y., Tanaka, S., Jimi, E., Oda, H., Katagiri, T.
  • Organizer: Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Research Meeting
  • Int'l Joint Research
• [Presentation] An antibody against ALK2 extracellular domain reveals a role of dimer formation for signal activation. (2018)
  • Author(s): Katagiri, T., Tsuji, S., Tsukamoto, S., Kuratani, M., Ohte, S., Takaishi, K., Nakamura, K., Kawaguchi, Y., Hasegawa, J.
  • Organizer: ASBMR 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] A novel crosstalk between BMP and Wnt7b in postnatal endochondral ossification. (2018)
  • Author(s): Tsukamoto, S., Kuratani, M., Sekine, N., Okubo, M., Nakachi, Y., Tanaka, S., Jimi E., Oda, H., Katagiri, T.
  • Organizer: 12th International BMP Conference
  • Int'l Joint Research
• [Presentation] Expression levels of BMP ligands are increased by muscle trauma. (2018)
  • Author(s): Kuratani, M., Tsukamoto, S., Sekine, N., Okubo, M., Nakachi, Y., Katagiri, T.
  • Organizer: 12th International BMP Conference
  • Int'l Joint Research
• [Presentation] A role of dimer formation of ALK2, a BMP type I receptor, in the activation of intracellular signaling. (2018)
  • Author(s): Katagiri, T., Tsuji, S., Tsukamoto, S., Kuratani, M., Ohte, S., Takaishi, K., Nakamura, K., Kawaguchi, Y., Hasegawa, J.
  • Organizer: Gordon Research Conference on Cartilage
  • Int'l Joint Research
• [Presentation] 筋肉が骨に変わる難病の克服に向けて (2018)
  • Author(s): 片桐岳信
  • Organizer: 飯能ロータリークラブ講演会
  • Invited
• [Presentation] A connection between bone and muscle by BMPs. (2018)
  • Author(s): Katagiri, T.
  • Organizer: Seminar at University of California Davis
  • Int'l Joint Research / Invited
• [Presentation] 進行性骨化性線維異形成症（FOP）に対する革新的治療薬の創出 (2018)
  • Author(s): 片桐岳信
  • Organizer: 第16回RCGM国際フロンティアシンポジウム
  • Int'l Joint Research / Invited
• [Presentation] FOPの克服に向けて (2018)
  • Author(s): 片桐岳信
  • Organizer: 第12回 国際BMPカンファレンス 市民公開講座 FOPを治す！～研究者から患者へのメッセージ～
  • Invited
• [Presentation] Bone morphogenetic proteins: critical regulators of bone formation. (2018)
  • Author(s): Katagiri, T
  • Organizer: 12th International BMP Conference
  • Int'l Joint Research / Invited
• [Presentation] Gift from C2C12 myoblasts. (2018)
  • Author(s): Katagiri, T
  • Organizer: 12th International BMP Conference
  • Int'l Joint Research / Invited
• [Presentation] Development of blocking antibodies against ALK2 for fibrodysplasia ossificans progressiva. (2018)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Kuratani M, Ohte S, Sekine N, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y
  • Organizer: Gordon Research Conference on Bones and Teeth
  • Int'l Joint Research / Invited
• [Presentation] Development of blocking antibodies against ALK2 for fibrodysplasia ossificans progressiva. (2018)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Kuratani M, Ohte S, Sekine N, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y
  • Organizer: Gordon Research Conference on Antibody Biology and Engineering
  • Int'l Joint Research
• [Presentation] 生理的および病的な骨形成を制御するBMP研究の最前線 (2017)
  • Author(s): 片桐岳信
  • Organizer: 第90回日本内分泌学会
  • Invited
• [Presentation] 進行性骨化性線維異形成症の病態解明に基づく治療薬開発 (2017)
  • Author(s): 片桐岳信
  • Organizer: 第59回歯科基礎医学会学術大会 メインシンポジウムA
  • Invited
• [Presentation] Update of an anti-ALK2 blocking antibody. (2017)
  • Author(s): Katagiri T
  • Organizer: FOP Drug Development Forum 2017
  • Int'l Joint Research / Invited
• [Presentation] FOPの創薬に向けた取り組み (2017)
  • Author(s): 片桐岳信
  • Organizer: FOP研究班報告会
  • Invited
• [Presentation] 進行性骨化性線維異形成症FOPの克服に向けた取り組み (2017)
  • Author(s): 片桐岳信
  • Organizer: 第15回RCGMフロンティアシンポジウム
  • Invited
• [Presentation] 難病FOP研究の最先端. (2017)
  • Author(s): 片桐岳信
  • Organizer: 九州歯科大学大学院セミナー
  • Invited
• [Presentation] BMPのI型受容体ALK2に対する特異的阻害抗体の開発. (2017)
  • Author(s): 片桐岳信、辻真之介、塚本翔、大手聡、熊谷桂吾、大澤賢次、高石巨澄、中村健介、川口喜朗、長谷川淳
  • Organizer: 第3回日本骨免疫学会
• [Presentation] Development of blocking monoclonal antibodies against ALK2, which is a type I receptor for BMPs. (2017)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Ohte S, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y, Hasegawa J
  • Organizer: 2017 FASEB Science Research Conferences on The TGF-β Superfamily
  • Int'l Joint Research
• [Presentation] Analysis of skeletal growth in Smad4 knockout mice. (2017)
  • Author(s): Tsukamoto S, Sekine N, Kuratani M, Kumagai K, Tanaka S, Jimi E, Oda H, Katagiri T
  • Organizer: 2017 FASEB Science Research Conferences on The TGF-β Superfamily
  • Int'l Joint Research
• [Presentation] 軟組織における異所性骨化を誘導するBMP受容体ALK2に対する特異的阻害抗体の開発 (2017)
  • Author(s): 片桐岳信、辻真之介、塚本翔、大手聡、熊谷桂吾、大澤賢次、高石巨澄
  • Organizer: 第35回日本骨代謝学会学術集会
• [Presentation] Development of blocking monoclonal antibodies against ALK2, which is a type I receptor for BMPs. (2017)
  • Author(s): Katagiri T, Tsuji S, Tsukamoto S, Ohte S, Kumagai K, Osawa K, Takaishi K, Nakamura K, Kawaguchi Y, Hasegawa J
  • Organizer: 2017 ASBMR Annual Meeting
  • Int'l Joint Research
• [Presentation] ostnatal ablation of Smad4 enhances endochondral ossification in epiphyseal growth plate. (2017)
  • Author(s): Tsukamoto S, Sekine N, Kuratani M, Kumagai K, Tanaka S, Jimi E, Oda H, Katagiri T
  • Organizer: 2017 ASBMR Annual Meeting
  • Int'l Joint Research
• [Presentation] Analysis of skeletal phenotypes in Smad4 conditional knockout mice. (2017)
  • Author(s): Tsukamoto S, Sekine N, Kuratani M, Kumagai K, Jimi E, Katagiri T
  • Organizer: The 65th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research
• [Presentation] Analysis of the TGF-β family ligands that are increased in regenerating skeletal muscle and induce BMP signaling via a mutant ALK2 associated with fibrodysplasia ossificans progressiva. (2017)
  • Author(s): Kuratani M, Tsukamoto S, Katagiri T
  • Organizer: The 65th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research
• [Presentation] 転写共役因子Smad4は軟骨細胞分化を介して骨形成を制御する. (2017)
  • Author(s): 塚本翔、関根典子、倉谷麻衣、熊谷桂吾、大久保美里、片桐岳信
  • Organizer: 第15回RCGMフロンティアシンポジウム
• [Presentation] BMP受容体ALK2が誘導する異所性骨化モデルの構築 (2017)
  • Author(s): 倉谷麻衣、塚本翔、関根典子、片桐岳信
  • Organizer: 第15回RCGMフロンティアシンポジウム
• [Remarks] 埼玉医科大学FOP診療・研究プロジェクト
  • URL: http://www.saitama-med.ac.jp/medlinks/saitama_univ_fop/index.html
• [Remarks] 埼玉医科大学医学部基礎医学
  • URL: http://www.saitama-med.ac.jp/uinfo/biomedsci/index.html
• [Remarks] 埼玉医科大学ゲノム医学研究センター病態生理部門
  • URL: http://www.saitama-med.ac.jp/genome/Div04_PPhysiol/index.html
• [Remarks] 埼玉医科大学ゲノム医学研究センター 病態生理部門
  • URL: http://www.saitama-med.ac.jp/genome/Div04_PPhysiol/index.html
• [Patent(Industrial Property Rights)] 骨形成促進作用を有する物質のスクリーニング方法、並びにGpr124及びReckの少なくともいずれかを発現する細胞を含む細胞集団の調製方法 (2018)
  • Inventor(s): 片桐岳信、塚本 翔
  • Industrial Property Rights Holder: 学校法人埼玉医科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-113327
  • Filing Date: 2018