CIZ regulates anabolic action of PTH on bone

• Project/Area Number: 22591680
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAKAMOTO Tetsuya 東京医科歯科大学, 歯と骨のGCOE拠点, GCOE拠点形成特任教員 (90334383)
• Co-Investigator(Kenkyū-buntansha): HAYATA Tadayoshi 東京医科歯科大学, 難治疾患研究所, 助教 (40420252)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨・軟骨代謝学 / 骨粗鬆症 / CIZ / PTH / BMP / 副甲状腺ホルモン / 骨形成 / PPR

Research Abstract

We analyzed the involvement of CIZ, a BMP-inhibitory factor, in PTH-signaling. The caPPR mice express constitutively active PTH/PTHrP receptor (caPPR) in osteoblasts and in odontoblasts, and exhibit increased bone volume. The CIZKO mice also show increased bone volume. We crossed caPPR mice with CIZKO and caPPR-CIZKO mice exhibited further increased bone volume in our preliminary experiments.
We had difficulties in expanding the number of caPPR-CIZKO mice, because caPPR mice are weak and because CIZKO mice have defect in spermatogenesis as reported. However, we finally got 6-10 mice in each group of 4 genotypes x 2 sex.
In cell culture system, we used MC-3T3E1 cells, a osteoblast-like cell line. In order to analyze the transcriptional activity of CRE (cAMP response element), we transfected cellswith pCre-Luc vector and performed luciferase assays. When CIZ was overexpressed, caPPR-induced increase of CRE-activity did not show changes. CIZ inhibits BMP signal and PTH are reported to enhance BMP signals. Therefore we speculate that CIZ does not directly inhibit PTH-induced bone increase but that CIZ affects PTH-induced bone increase by way of inhibiting BMP signaling.

Research Products

• [Journal Article] Nck1 Deficiency Accelerates Unloading-Induced Bone Loss (2013)
  • Author(s): Aryal A. C. S, Miyai K, Hayata T, Notomi T, Nnakamoto T, Pawson T, Ezura Y, Noda M.
  • Journal Title: Journal of Cellular Physiology Volume: 228 Issue: 7 Pages: 1397-403
  • DOI: 10.1002/jcp.24317
  • Peer Reviewed
• [Journal Article] Osteoblastic differentiation enhances expression of TRPV4 that is required for calcium oscillation induced by mechanical force (2013)
  • Author(s): Suzuki T, Notomi T, Miyajima D, Mizoguchi F, Hayata T, Nakamoto T, Hanyu R, Kamolratanakul P, Mizuno A, Suzuki M, Ezura Y, Izumi Y, Noda M
  • Journal Title: Bone Volume: 54 Pages: 172-178
  • Peer Reviewed
• [Journal Article] Type VI collagen deficiency induces osteopenia with distortion of osteoblastic cell morphology (2012)
  • Author(s): Izu, Y., Ezura, Y., Mizoguchi, F., Kawamata, A., Nakamoto, T., Nakashima, K., Hayata, T., Hemmi, H., Bonaldo, P., and Noda, M
  • Journal Title: Tissue & cell Volume: 44 Issue: 1 Pages: 1-6
  • DOI: 10.1016/j.tice.2011.08.002
  • Peer Reviewed
• [Journal Article] CIZ/NMP4 is expressed in B16 melanoma and forms a positive feedback loop with RANKL to promote migration of the melanoma cells (2012)
  • Author(s): Sakuma, T., Nakamoto, T., Hemmi, H., Kitazawa, S., Kitazawa, R., Notomi, T., Hayata, T., Ezura, Y., Amagasa, T., and Noda, M
  • Journal Title: Journal of cellular physiology Volume: 227 Issue: 7 Pages: 2807-2812
  • DOI: 10.1002/jcp.24066
  • Peer Reviewed
• [Journal Article] Anabolic action of parathyroid hormoneregulated by the beta2-adrenergic receptor (2012)
  • Author(s): Hanyu R, Wehbi VL, Hayata T, Moriya S, Feinstein TN, Ezura Y, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Takeda S, Kaneko K, Kurosawa H, Karsenty G, Kronenberg HM, Vilardaga JP, Noda M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 7433-7438
  • Peer Reviewed
• [Journal Article] Profilin1 regulates sternum development and endochondral bone formation (2012)
  • Author(s): Miyajima D, Hayata T, Suzuki T, Hemmi H, Nakamoto T, Notomi T, Amagasa T, Bottcher RT, Costell M, Fassler R, Ezura Y, Noda M
  • Journal Title: J Biol Chem Volume: 287 Issue: 40 Pages: 33545-33553
  • DOI: 10.1074/jbc.m111.329938
• [Journal Article] Anabolic action of parathyroid hormone regulated by the beta2-adrenergic receptor (2012)
  • Author(s): Hanyu, R.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Issue: 19 Pages: 7433-7438
  • DOI: 10.1073/pnas.1109036109
  • Peer Reviewed
• [Journal Article] Per-1 is a specific clock gene regulated byparathyroid hormone (PTH) signaling in osteoblasts and is functional for the transcriptional events induced by PTH (2011)
  • Author(s): Hanyu, R., Hayata, T., Nagao, M., Saita, Y., Hemmi, H., Notomi, T., Nakamoto, T., Schipani, E., Knonenbery, H., Kaneko, K., Kurosawa, H., Ezura, Y., Noda, M
  • Journal Title: J Cell Biochem Volume: 112 Issue: 2 Pages: 433-438
  • DOI: 10.1002/jcb.22957
  • Peer Reviewed
• [Journal Article] Schnurri-2 deficiency counteracts against bone loss induced by ovariectomy (2011)
  • Author(s): Nagao, M., Saita, Y., Hanyu, R., Hemmi, H., Notomi, T., Hayata, T., Nakamoto, T., Nakashima, K., Kaneko, K., Kurosawa, H., Ishii, S., Ezura, Y., Noda, M
  • Journal Title: J Cell Physiol Volume: 226 Issue: 3 Pages: 573-538
  • DOI: 10.1002/jcp.22521
  • Peer Reviewed
• [Journal Article] Nanogel-Based Scaffold Delivery of Prostaglandin E2 Receptor-Specific Agonist in Combination With a Low Dose of Growth Factor Heals Critical-Size Bone Defects in Mice (2011)
  • Author(s): P.Kamolratanakul, et al
  • Journal Title: Arthritis and Rheumatism Volume: 63 Issue: 4 Pages: 1021-1033
  • DOI: 10.1002/art.30151
  • Peer Reviewed
• [Journal Article] Osteopontin deficiency enhances parathyroid hormone/ parathyroid hormone related peptide receptor (PPR) signaling-induced alteration in tooth formation and odontoblastic morphology (2011)
  • Author(s): Morishita, M., Ono N., Miyai, K., Nakagawa, T., Hanyu, R., Nagao, M.,Kamolratanakul, P., Notomi, T., Rittling, S. R., Denhardt, D. T., Kronenberg, H. M., Ezura, Y., Hayata, T., Nakamoto, T., and Noda, M
  • Journal Title: Tissue & cell Volume: 43 Issue: 3 Pages: 196-200
  • DOI: 10.1016/j.tice.2011.02.003
  • Peer Reviewed
• [Journal Article] MURF1 deficiency suppresses unloading-induced effects on osteoblasts and osteoclasts to lead to bone loss (2011)
  • Author(s): Kondo H, Ezura Y, Nakamoto T, Hayata T, Notomi T, Sorimachi H, Takeda S, Noda M
  • Journal Title: J Cell Biochem Volume: 112(12) Issue: 12 Pages: 3525-30
  • DOI: 10.1002/jcb.23327
  • Peer Reviewed
• [Journal Article] Cas-L regulates myeloid cell motility and suppresses progression of leukemia induced by p210Bcr/Abl (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Cancer Science Volume: 102 Issue: 12 Pages: 2109-2117
  • DOI: 10.1111/j.1349-7006.2011.02066.x
  • Peer Reviewed
• [Journal Article] Sympathetic control of bone mass regulated by osteopontin (2011)
  • Author(s): Nagao, M., Feinstein, T. N., Ezura, Y., Hayata, T., Notomi, T., Saita, Y., Hanyu, R., Hemmi, H., Izu, Y., Takeda, S., Wang, K., Rittling, S., Nakamoto, T., Kaneko, K., Kurosawa, H., Karsenty, G., Denhardt, D. T., Vilardaga, J. P., and Noda, M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 43 Pages: 17767-17772
  • DOI: 10.1073/pnas.1109402108
  • Peer Reviewed
• [Journal Article] Nanogel-based scaffold delivery of prostaglandin E(2)receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice. (2011)
  • Author(s): Kamolratanakul P, Hayata T, Ezura Y, Kawamata A, Hayashi C, Yamamoto Y, Hemmi H, Nagao M, Hanyu R, Notomi T, Nakamoto T, Amagasa T, Akiyoshi K, Noda M
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 1021-1033
  • Peer Reviewed
• [Journal Article] Per-1 is a specific clock gene regulated by parathyroid hormone(PTH)signaling in osteoblasta and is functional for the tranacriptional events induced by PTH. (2011)
  • Author(s): Hanyu R, Hayata T, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Knonenbery H, Kaneko K, Kurosawa H, Ezura Y, Noda M.
  • Journal Title: J Cell Biochem Volume: 112 Pages: 433-438
  • Peer Reviewed
• [Journal Article] Schnurri-2 deficiency counteracts against bone lose induced by ovariectomy. (2011)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hemmi H, Notomi T, Hayata T, Nakamoto T, Nakashima K, Kaneko K, Kurosawa H, Ishii S, Ezura Y, Noda M
  • Journal Title: J Cell Physiol Volume: 226 Pages: 573-578
  • Peer Reviewed
• [Presentation] Chondrocyte Metabolism in Inflammatory Arthritis is regulated by CIZ (2012)
  • Author(s): Tetsuya Nakamoto, Takayuki Motoyoshi, Tasuku Hada, Makiri Kawasaki, Tomomi Sakuma, Tadayoshi Hayata, Yoichi Ezura, Masaki Noda
  • Organizer: ASBMR 2012 Annual Meeting
  • Place of Presentation: ミネアポリス、米国
  • Year and Date: 2012-10-15
• [Presentation] Kronenberg、 野田政樹PTHの骨形成促進作用はシャトリン グタンパク質CIZによって抑制される (2012)
  • Author(s): 中元哲也、平林恭子、AlexanderValentinitsch、川崎真希理、佐久間朋美、早田匡芳、江面陽一、ErnestinaSchipani、Henry M
  • Organizer: 第30回日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2012-07-21
• [Presentation] PTHの骨形成促進作用はシャトリングタンパク質CIZによって抑制される (2012)
  • Author(s): 中元哲也
  • Organizer: 第30回日本骨代謝学会学術集会
  • Place of Presentation: 東京
• [Presentation] Molecular mechanism of CIZ actions to exacerbate inflammation in serum-induced arthritis based on formation of positive feedback loop with IL-1 beta (2011)
  • Author(s): Nakamoto T,.Motoyoshi T, Kawasaki M, Sakuma T, Hayata T, Ezura Y, Noda M
  • Organizer: ASBMR2011 Annual Meeting
  • Place of Presentation: San Diego Convention Center, SanDiego, CA USA
  • Year and Date: 2011-09-16
• [Presentation] Role of CIZ in melanoma activity for metastasis (2011)
  • Author(s): Hemmi H, Notomi T, Nakamoto T, Hayata T, Ezura Y, Sakuma T, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA USA
  • Year and Date: 2011-09-16
• [Presentation] Molecular mechanism of CIZ actions to exacerbate inflammation in serum-induced arthritis based on formation of positive feedback loop with IL-1 beta (2011)
  • Author(s): Nakamoto T, Motoyoshi T, Kawasaki M, Sakuma T, Hayata T, Ezura Y, Noda M
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA USA
  • Year and Date: 2011-09-16
• [Presentation] CIZ と IL-1ssは相互に発現を誘導し、 関節炎に関与する (2011)
  • Author(s): 中元哲也、元吉貴之、川崎真希理、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-29
• [Presentation] 軟骨細胞ATDC5において炎症誘導因子LPSはIL-1ssによるCIZ発現を制御する (2011)
  • Author(s): 川崎真希理、中元哲也、納富拓也、早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-29
• [Presentation] CIZとIL-1βは相互に発現を誘導し、関節炎に関与する (2011)
  • Author(s): 中元哲也、元吉貴之、川崎真希理、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-29
• [Presentation] 軟骨細胞ATDC5において炎症誘導因子LPSはIL-1βによるCIZ発現を制御する (2011)
  • Author(s): 川崎真希理、中元哲也、納富拓也、早田匡芳、江面陽一、野田政樹
  • Organizer: 第29回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-07-29
• [Presentation] CIZは悪性黒色腫細胞の転移に促進的に働く (2010)
  • Author(s): 佐久間朋美,中元哲也,宮井健太郎,辺見弘明,天笠光雄,早田匡芳,江面陽一,野田政樹
  • Organizer: BMB2010
  • Place of Presentation: ポートピアホテル(神戸)
  • Year and Date: 2010-12-08
• [Presentation] CIZは悪性黒色腫細胞の転移に促進的に働く (2010)
  • Author(s): 佐久間朋美, 中元哲也, 宮井健太郎, 辺見弘明, 天笠光雄, 早田匡芳, 江面陽一, 野田政樹
  • Organizer: BMB 2010
  • Place of Presentation: ポートピアホテル(神戸)
  • Year and Date: 2010-12-08
• [Presentation] CIZ Express ion is Enhanced by Inflammatory Stimu lation and Transcriptionally Regulates t he RANKL Promoter (2010)
  • Author(s): T. Nakamoto, T. Hada, T. Motoyoshi, T.Sakuma, T. Hayata, Y. Ezura, R. Kitaza wa, S Kitazawa, M Noda
  • Organizer: ASBMR 2010
  • Place of Presentation: コンベンションセンター (トロント、カナダ)
  • Year and Date: 2010-10-17
• [Presentation] CIZ Expression is Enhanced by Inflammatory Stimulation and Transcriptionally Regulates the RANKL Promoter (2010)
  • Author(s): T.Nakamoto, T.Hada, T.Motoyoshi, T.Sakuma, T.Hayata, Y.Ezura, R.Kitazawa, Sohei Kitazawa, Masaki Noda
  • Organizer: ASBMR 2010
  • Place of Presentation: コンベンションセンター(トロント、カナダ)
  • Year and Date: 2010-10-17
• [Presentation] CIZの欠損は、関節炎進展を抑制する (2010)
  • Author(s): 中元哲也、羽田佑、元吉貴之、佐久間朋美、早田匡芳、江面陽一、野田政樹
  • Organizer: 第28回日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2010-07-21
• [Book] Tetsuya Nakamoto, Takuya Notomi and Yoichi Ezura Mechanosensing Biology: Mechanical Stress and Bone Springer (2011)
  • Author(s): Masaki Noda
  • Total Pages: 16
  • Publisher: Tadayoshi Hayata
• [Book] Mechanosensing Biology: Mechanical Stress and Bone (2011)
  • Author(s): Masaki Noda, Tadayoshi Hayata, Tetsuya Nakamoto, Takuya Notomi, Yoichi Ezura
  • Total Pages: 16
  • Publisher: Springer