Analysis of a novel regulation of BMP signaling by Smad8

• Project/Area Number: 25893228
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Saitama Medical University
• Principal Investigator: TSUKAMOTO SHO 埼玉医科大学, 医学部, 助手 (20707658)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨・軟骨代謝学 / シグナル伝達 / 骨系統疾患 / 骨、軟骨代謝学

Outline of Final Research Achievements

Smad proteins are transcription factors important for bone formation regulated by BMPs. Smad1, Smad5 and Smad8 (also known as Smad9) are induced phosphorylation by BMP receptors. We have established constitutively active forms of Smad1, Smad5 and Smad8 and found that Smad8 is less active than other Smads. The mRNA levels of Smad8 mRNA were increased by BMP-4 stimulation. RNAi knockdown of Smad8 increased the BMP-induced ALP activity in C2C12 cells. Therefore, Smad8 suppressed BMP activity via a novel molecular mechanism. Smad8 bound to Smad1 with a higher affinity than that of Smad1 homodimer. Taken together, our findings suggest that Smad8 represses intracellular BMP signaling as a dominant negative Smad.

Research Products

• [Journal Article] Mutant activin-like kinase 2 in fibrodysplasia ossificans progressiva are activated via T203 by BMP type II receptor (2015)
  • Author(s): Fujimoto M, Ohte S, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Suda N, Katagiri T
  • Journal Title: Mol Endocrinol Volume: 29 Issue: 1 Pages: 140-152
  • DOI: 10.1210/me.2014-1301
  • Peer Reviewed / Open Access
• [Journal Article] Bone morphogenetic protein-induced heterotopic bone formation: What have we learned from the history of a half century? (2015)
  • Author(s): Katagiri T, Osawa K, Tsukamoto, Fujimoto M, Miyamoto A, Mizuta T.
  • Journal Title: Jpn Dent Sci Rev Volume: 51 Issue: 2 Pages: 42-50
  • DOI: 10.1016/j.jdsr.2014.09.004
  • NAID: 50009645833
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Machiya A, Jimi E, Kokabu S, Katagiri T.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 7596-7596
  • DOI: 10.1038/srep07596
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2. (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Machiya A, Okuda A, Suda N, Katagiri T.
  • Journal Title: Biochmical and Biophysical Research Communications Volume: 455 Issue: 3-4 Pages: 347-352
  • DOI: 10.1016/j.bbrc.2014.11.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling (2014)
  • Author(s): Kokabu S, Sato T, Ohte S, Enoki Y, Okubo M, Katagiri T, Rosen V, Yoda T.
  • Journal Title: Federation of European Biochemical Societies letters Volume: 588 Issue: 4 Pages: 614-619
  • DOI: 10.1016/j.febslet.2013.12.031
  • Peer Reviewed
• [Journal Article] TGF-βファミリーからみえる 骨と筋の新しい接点 (2014)
  • Author(s): 片桐岳信、塚本翔、大澤賢次
  • Journal Title: 実験医学 (増刊) Volume: 32 Pages: 1010-1016
• [Presentation] Smad9 is a new type of transcriptional repressor in BMP signaling (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉医科大学30周年記念講堂(埼玉県 日高市)
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Chondrogenic differentiation of murine embryonic stem cells carrying an active form of ALK2 (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Mizuta T, Osawa K, Tsukamoto S, Miyamoto A, Okuda A, Suda N, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉医科大学30周年記念講堂(埼玉県 日高市)
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Establishment of a new model of chondrogenesis using skeletal muscle cells (2014)
  • Author(s): Miyamoto A, Osawa K, Tsukamoto S, Fujimoto M, Mizuta T, Ohte S, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉医科大学30周年記念講堂(埼玉県 日高市)
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Establish of a new Luciferase reporter plasmid for monitoring intracellular signaling of non-osteogenic members of the TGF-β family (2014)
  • Author(s): Mizuta T, Tsukamoto S, Fujimoto M, Miyamoto A, Osawa K, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉医科大学30周年記念講堂(埼玉県 日高市)
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Establishment of a new in vivo experimental model for heterotopic bone formation in skeletal muscle (2014)
  • Author(s): Osawa K, Tsukamoto S, Fujimoto M, Miyamoto A, Mizuta T, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉医科大学30周年記念講堂(埼玉県 日高市)
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Smad8 is a novel regulator of BMP signaling (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: 10th International BMP Conference
  • Place of Presentation: ベルリン(ドイツ)
  • Year and Date: 2014-09-16 – 2014-09-20
• [Presentation] Smad8 negatively regulates BMP signaling in a dominant negative fashion (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: 2014 ASBMR Annual Meeting
  • Place of Presentation: ヒューストン(アメリカ)
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Establishment and characterization of a novel Tet-Off embryonic stem cell lines carrying ALK2 (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Tsukamoto S, Miyamoto A, Mizuta T, Kokabu S, Okuda A, Suda N, Katagiri T
  • Organizer: 2014 ASBMR Annual Meeting
  • Place of Presentation: ヒューストン(アメリカ)
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Smad8による新たなBMPシグナルの制御機構 (2014)
  • Author(s): 塚本翔、水田誉人、藤本舞、大手聡、大澤賢次、宮本阿礼、米山克美、村田栄子、自見英治郎、古株彰一郎、片桐岳信
  • Organizer: 第21回BMP研究会
  • Place of Presentation: 大阪大学 中ノ島センター(大阪府 大阪市)
  • Year and Date: 2014-07-27
• [Presentation] A novel regulation of BMP signaling by Smad8 (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: FASEB Science Research Conferences Skeletal Muscle Satellite and Stem Cells
  • Place of Presentation: スティームボート・スプリングズ(アメリカ)
  • Year and Date: 2014-07-20 – 2014-07-25
• [Presentation] Establishment of a novel model for chondrogenic differentiation using murine embryonic stem cells carrying mutant ALK2 (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Tsukamoto S, Miyamoto A, Mizuta T, Kokabu S, Okuda A, Suda N, Katagiri T
  • Organizer: FASEB Science Research Conferences Skeletal Muscle Satellite and Stem Cells
  • Place of Presentation: スティームボート・スプリングズ(アメリカ)
  • Year and Date: 2014-07-20 – 2014-07-25
• [Presentation] Smad8 is a Novel Type Regulator of BMP Signaling (2013)
  • Author(s): Sho Tsukamoto, Satoshi Ohte, Mai Fujimoto, Takato Mizuta, Arei Miyamoto, Kenji Osawa, Shoichiro Kokabu, Eiko Murata, Eijiro Jimi, Takenobu Katagiri
  • Organizer: 2013 ASBMR Symposium Cutting Edge Discoveries in Muscle Biology, Disease and Therapeutics
  • Place of Presentation: ボルチモア (アメリカ)
• [Presentation] Smad8 is a Novel Type Regulator of BMP Signaling (2013)
  • Author(s): Sho Tsukamoto, Satoshi Ohte, Mai Fujimoto, Takato Mizuta, Arei Miyamoto, Kenji Osawa, Shoichiro Kokabu, Eiko Murata, Eijiro Jimi, Takenobu Katagiri
  • Organizer: 2013 ASBMR Annual Meeting
  • Place of Presentation: ボルチモア (アメリカ)
• [Presentation] 転写因子Smad8によるBMPシグナル調節機構の解明 (2013)
  • Author(s): 塚本翔、水田誉人、大澤賢次、藤本舞、宮本阿礼、片桐岳信
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉 日高市
• [Presentation] TGF-bのI型受容体における活性化機序の解析 (2013)
  • Author(s): 水田誉人、塚本翔、藤本舞、宮本阿礼、大澤賢次、片桐岳信
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉 日高市
• [Presentation] 進行性骨化性線維異形成症(FOP)におけるALK2変異体の活性化メカニズムの解析 (2013)
  • Author(s): 藤本舞、塚本翔、大澤賢次、宮本阿礼、水田誉人、須田直人、片桐岳信
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉 日高市
• [Presentation] FOPの変異ALK2は異所性骨化を誘導する (2013)
  • Author(s): 大澤賢次、宮本阿礼、塚本翔、藤本舞、水田誉人、片桐岳信
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉 日高市
• [Presentation] マウス骨格筋由来細胞によるALK2(R206H)の新しい解析法の樹立 (2013)
  • Author(s): 宮本阿礼、大澤賢次、塚本翔、藤本舞、水田誉人、片桐岳信
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉 日高市