Pathological study on metalloproteinases in tissue remodeling under pathological conditions

• Project/Area Number: 24249022
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Keio University
• Principal Investigator: OKADA Yasunori 慶應義塾大学, 医学部, 教授 (00115221)
• Co-Investigator(Kenkyū-buntansha): MOCHIZUKI Satsuki 慶應義塾大学, 医学部, 専任講師 (80365428) ; FUJII Yutaka 福井大学, 医学部, 教授 (80211522) ; SHIMODA Masayuki 慶應義塾大学, 医学部, 専任講師 (70383734) ; KIMURA Tokuhiro 慶應義塾大学, 医学部, 助教 (40445200)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥46,280,000 (Direct Cost: ¥35,600,000、Indirect Cost: ¥10,680,000); Fiscal Year 2014: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2013: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2012: ¥21,060,000 (Direct Cost: ¥16,200,000、Indirect Cost: ¥4,860,000)
• Keywords: MMP / ADAM / TIMP / 組織リモデリング / 悪性腫瘍 / 急性大動脈解離 / 変形性関節症 / 関節軟骨 / EMT / 血管

Outline of Final Research Achievements

We have studied the roles of metalloproteinases in pathological tissue remodeling, and obtained the following data: 1) ADAM28 produced by lung carcinoma cells plays a key role in cancer cell proliferation and metastasis and this molecule seems to be a good drug target for the treatment of non-small cell lung cancers. 2) Activities of metalloproteinases derived from cancer-associated fibroblasts control cancer cell proliferation, invasion and metastasis. 3) Neutrophil-derived MMP-9 has an important role in the initiation of acute aortic dissection, which is an extremely intractable disease with poor prognosis. 4) The activity of ADAMTS4, which is a major metalloproteinase implicated for aggrecan degradation in human osteoarthritis (a major cause of locomotive syndrome), is inhibited by CCN1(Cyr61) and KIAA1199 is a key enzyme for hyaluronan depolymerization.

Research Products

• [Journal Article] Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas. (2015)
  • Author(s): Mikami S., Mizuno R., Kosaka T., Saya H., Oya M. and Okada Y.
  • Journal Title: Int J Cancer Volume: 136 Pages: 1504-1514
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. (2015)
  • Author(s): Anzai A., Shimoda M., Endo J., Kohno T., Katsumata ., Matsuhashi T., Yamamoto T., Ito K., Yan X., Shirakawa K., Shimizu-Hirota R., Yamada Y., Ueha S., Shinmura K., Okada Y., Fukuda K. and Sano M.
  • Journal Title: Circ Res Volume: 116 Pages: 612-623
  • Peer Reviewed
• [Journal Article] Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. (2015)
  • Author(s): Ishida M., Mikami S., Shinojima T., Kosaka T., Mizuno R., Kikuchi E., Miyajima A., Okada Y. and Oya M.
  • Journal Title: Int J Cancer Volume: in press
  • Peer Reviewed
• [Journal Article] CCN1 (Cyr61) is overexpressed in human osteoarthritic cartilage and inhibits ADAMTS4 (aggrecanase-1) activity. (2015)
  • Author(s): Chijiiwa M., Mochizuki S., Kimura T., Abe H., Tanaka Y., Fujii Y., Shimizu H., Enomoto H., Toyama Y. and Okada Y.
  • Journal Title: Arthritis Rheum Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Invasion and metastasis of renal cell carcinoma. (2014)
  • Author(s): Mikami S., Oya M., Mizuno R., Kosaka T., Katsube K. I. and Okada Y.
  • Journal Title: Med Mol Morphol Volume: 47 Pages: 63-67
  • Peer Reviewed
• [Journal Article] Heat-induced antigen retrieval in conventionally processed epon-embedded specimens: procedures and mechanisms. (2014)
  • Author(s): Yamashita S. and Okada Y.
  • Journal Title: J Hictochem Cytochem Volume: 62 Pages: 584-597
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of the TIMP gene family is sufficient for the acquisition of the CAF-like cell state. (2014)
  • Author(s): Shimoda M., Principe S., Jackson H.W., Luga V., Fang H., Molyneux S.D., Shao Y.W., Aiken A., Waterhouse P.D., Karamboulas C., Hess F.M., Ohtsuka T., Okada Y., Ailles L., Ludwig A., Wrana J.L., Kislinger T. and Kohkha R.
  • Journal Title: Nat Cell Biol Volume: 16 Pages: 889-901
  • Peer Reviewed
• [Journal Article] Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones (2013)
  • Author(s): Saito K, Horiuchi K, Kimura T, Mizuno S, Yoda M, Morioka H, Akiyama H, Threadgill D, Okada Y, Toyama Y, Sato K
  • Journal Title: PLoS One Volume: 8(1) Issue: 1 Pages: e54853-e54853
  • DOI: 10.1371/journal.pone.0054853
  • Peer Reviewed
• [Journal Article] Systemic overexpression of TNFα-converting enzyme does not lead to enhanced shedding activity in vivo (2013)
  • Author(s): Yoda M, Kimura T, Tohmonda T, Morioka H, Matsumoto M, Okada Y, Toyama Y, Horiuchi K
  • Journal Title: PLoS One Volume: 8(1) Issue: 1 Pages: e54412-e54412
  • DOI: 10.1371/journal.pone.0054412
  • Peer Reviewed
• [Journal Article] KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. (2013)
  • Author(s): Yoshida H., Nagaoka A., Kusaka-Kikushima A., Tobiishi M., Kawabata K., Sayo T., Sakai S., Sugiyama Y., Enomoto H., Okada Y. and Inoue S.
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Issue: 14 Pages: 5612-5617
  • DOI: 10.1073/pnas.1215432110
  • Peer Reviewed
• [Journal Article] Src plays a role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells. (2013)
  • Author(s): Abe H., Mochizuki S., Ohara K., Ueno M., Ochiai H., Kitagawa Y., Hino O., Sato H. and Okada Y.
  • Journal Title: Am J Pathol Volume: 183 Issue: 5 Pages: 1667-1678
  • DOI: 10.1016/j.ajpath.2013.07.011
  • Peer Reviewed
• [Journal Article] HMGA2 is a driver of tumor metastasis. (2013)
  • Author(s): Morishita A., Zaidi M. R., Mitoro A., Sankarasharma D., Szabolcs M., Okada Y., D'Armiento J. and Chada K.
  • Journal Title: Cancer Res Volume: 73 Issue: 14 Pages: 4289-4299
  • DOI: 10.1158/0008-5472.can-12-3848
  • Peer Reviewed
• [Journal Article] Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse. (2013)
  • Author(s): Yamashita S., Kudo A., Kawakami H. and Okada Y.
  • Journal Title: Biol Reprod Volume: 88 Issue: 5 Pages: 1-13
  • DOI: 10.1095/biolreprod.112.106443
  • Peer Reviewed
• [Journal Article] Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelialcarcinoma. (2013)
  • Author(s): Shunsuke Yoshimine, Eiji Kikuchi, Takeo Kosaka, Shuji Mikami, Akira Miyajima, Yasunori Okada, Mototsugu Oya.
  • Journal Title: British Journal of Cancer (2013) Volume: 108 Issue: 11 Pages: 1-9
  • DOI: 10.1038/bjc.2013.216
  • Peer Reviewed
• [Journal Article] The prognostic significance of vasohibin-1 expression in patients with prostate cancer. (2013)
  • Author(s): Kosaka T, Miyazaki Y, Miyajima A, Mikami S, Hayashi Y, Tanaka N, Nagata H, Kikuchi E, Nakagawa K, Okada Y, Sato Y, Oya M
  • Journal Title: Br J Cancer. Volume: 108 Issue: 10 Pages: 2123-2129
  • DOI: 10.1038/bjc.2013.169
  • Peer Reviewed
• [Journal Article] Murine homologue of the human KIAA1199 is implicated in hyaluronan binding and depolymerization. (2013)
  • Author(s): Yoshida H., Nagaoka A., Nakamura S., Okada Y. and Inoue S.
  • Journal Title: FEBS Open Bio Volume: 3 Issue: 1 Pages: 352-356
  • DOI: 10.1016/j.fob.2013.08.003
  • Peer Reviewed
• [Journal Article] Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis. (2013)
  • Author(s): Nkyimbeng T., Ruppert C., Shiomi T., Dahal B.K., Lang G., Seeger W., Okada Y., D´Armiento J. and Gunther A.
  • Journal Title: PLoS One Volume: 8 Issue: 9 Pages: e73279-e73279
  • DOI: 10.1371/journal.pone.0073279
• [Journal Article] Regulatory Role of Dendritic Cells in Post-Infarction Healing and Left Ventricular Remodeling (2012)
  • Author(s): Anzai A, Fukuda K, et al
  • Journal Title: Circulation Volume: 125(10) Issue: 10 Pages: 1234-1245
  • DOI: 10.1161/circulationaha.111.052126
  • Peer Reviewed
• [Journal Article] High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm (2012)
  • Author(s): Kohno T., Anzai T., Kaneko H., Sugano Y., Shimizu H., Shimoda M., Miyasho T., Okamoto M., Yokota H., Yamada S., Yoshikawa T., Okada Y., Yozu R., Ogawa S. and Fukuda K
  • Journal Title: J Cardiol Volume: 59 Issue: 3 Pages: 299-306
  • DOI: 10.1016/j.jjcc.2012.01.007
  • NAID: 10031187749
  • Peer Reviewed
• [Journal Article] Effect of ADAM28 on Carcinoma Cell Metastasis by Cleavage of von Willebrand Factor (2012)
  • Author(s): Satsuki Mochizuki
  • Journal Title: Journal of the National Cancer Institute Volume: 104(In press) Issue: 12 Pages: 906-922
  • DOI: 10.1093/jnci/djs232
  • Peer Reviewed
• [Journal Article] Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha (2012)
  • Author(s): Nakayama M., Niki Y., Kawasaki T., Takeda Y., Horiuchi K., Sasaki A., Okada Y., Umezawa K., Ikegami H., Toyama Y. and Miyamoto T.
  • Journal Title: Arthritis Res Ther Volume: 14 Issue: 3
  • DOI: 10.1186/ar3850
  • Peer Reviewed
• [Journal Article] Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1receptor in prostate cancer (2012)
  • Author(s): Shirotake S, Miyajima A, Kosaka T, Tanaka N, Kikuchi E, Mikami S, Okada Y, Oya M
  • Journal Title: Am J Pathol. Volume: 180(3) Issue: 3 Pages: 1008-16
  • DOI: 10.1016/j.ajpath.2011.11.027
  • Peer Reviewed
• [Journal Article] Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection (2012)
  • Author(s): Kurihara T., Shimizu-Hirota R., Shimoda M., Adachi T., Shimizu H., Weiss S. J., Itoh H., Hori S., Aikawa N. and Okada Y
  • Journal Title: Circulation Volume: 126 Issue: 25 Pages: 3070-3080
  • DOI: 10.1161/circulationaha.112.097097
  • Peer Reviewed
• [Journal Article] ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α (2012)
  • Author(s): Jowett J.B.M., Okada Y., Leedman P.J., Curran J.E., Johnson M.P., Moses E.K., Goring H.H.H., Mochizuki S., Blangero J., Stone L., Allen H., Mitchell C. and Matthews V.B
  • Journal Title: Immunol Cell Biol Volume: 90 Issue: 10 Pages: 966-973
  • DOI: 10.1038/icb.2012.44
  • Peer Reviewed
• [Journal Article] Soluble Vascular Adhesion Protein-1 Accumulates in Proliferative Diabetic Retinopathy. (2012)
  • Author(s): Murata M, Noda K, Fukuhara J, Kanda A, Kase S, Saito W, Ozawa Y, Mochizuki S, Kimura S, Mashima Y, Okada Y, Ishida S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 53 Issue: 7 Pages: 4055-62
  • DOI: 10.1167/iovs.12-9857
  • Peer Reviewed
• [Presentation] OA関節軟骨代謝研究の過去と未来 (2015)
  • Author(s): 岡田保典
  • Organizer: 第28回日本軟骨代謝学会
  • Place of Presentation: 文京区、東京都、東京医科歯科大学
  • Year and Date: 2015-03-06 – 2015-03-07
  • Invited
• [Presentation] 創傷治癒の病理学―二次性創傷治癒におけるMMPの役割― (2014)
  • Author(s): 岡田保典
  • Organizer: 第16回日本褥瘡学会
  • Place of Presentation: 名古屋市、愛知県、名古屋国際会議場
  • Year and Date: 2014-08-29 – 2014-08-30
  • Invited
• [Presentation] OA関節軟骨の破壊と再生 (2014)
  • Author(s): 岡田保典
  • Organizer: 第6回日本関節鏡・膝・スポーツ整形外科学会
  • Place of Presentation: 広島市、広島県、広島国際会議場
  • Year and Date: 2014-07-25 – 2014-07-26
  • Invited
• [Presentation] CCN1 (Cyr61) is overexpressed in human osteoarthritic cartilage and inhibits ADAMTS4 (aggrecanase-1) activity. (2014)
  • Author(s): Chijiiwa M., Mochizuki S., Kimura T., Abe H., Tanaka Y., Fujii Y., Shimizu H., Enomoto H., Toyama. and Okada Y.
  • Organizer: Matrix Biology Europe 2014.
  • Place of Presentation: Rotterdam, Netherlands
  • Year and Date: 2014-06-20 – 2014-06-24
• [Presentation] 関節リウマチ関節破壊：現状とこれからの研究・治療への展望 (2013)
  • Author(s): 岡田保典
  • Organizer: 第57回日本リウマチ学会
  • Place of Presentation: 京都
  • Invited
• [Presentation] MMPs in diagnosis and pathogenesis of cardiovascular disease (2013)
  • Author(s): Yasunori Okada
  • Organizer: Gordon Research Conference on Matrix Metaloproteinases
  • Place of Presentation: Il Ciocco, Italy
  • Invited
• [Presentation] Promotion of cancer cell proliferation and metastasis by ADAM28 and possibility of ADAM28 target therapy (2013)
  • Author(s): 岡田保典
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 関節軟骨の破壊と再生機序 (2013)
  • Author(s): 岡田保典
  • Organizer: 第28回日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉
  • Invited
• [Presentation] Selective inhibition of ADAM28 activity by human anti-ADAM28 antibodies suppresses cancer cell proliferation and metastasis. (2013)
  • Author(s): Satsuki Mochizuki, Hitoshi Abe, Masyuki Shimoda, Noriko Aramaki-Hattori, Yuka Miyamae, Akira Miyakoshi, Kanehisa Kojoh and Yasunori Okada
  • Organizer: Pan Pacific Connective Tissue Society Symposium
  • Place of Presentation: Hong Kong.
• [Presentation] Aggrecanase-type ADAMTS species in human osteoarthritic cartilage: Expression and cytokine reactivity in chondrocytes and development of human neutralizing antibodies. (2013)
  • Author(s): Aya Shiraishi, Satsuki Mochizuki, Akira Miyakoshi, Kanehisa Kojoh and Yasunori Okada
  • Organizer: Pan Pacific Connective Tissue Society Symposium
  • Place of Presentation: Hong Kong.
• [Presentation] 変形性関節症関節軟骨の破壊と再生におけるメタロプロテアーゼの役割 (2013)
  • Author(s): 岡田保典
  • Organizer: 第25回日本軟骨代謝学会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 組織破壊とリモデリングの病理学的研究：統括病理学の時代を迎えて (2012)
  • Author(s): 岡田保典
  • Organizer: 第101回日本病理学会春期総会
  • Place of Presentation: 東京
  • Invited
• [Presentation] メタロプロテアーゼ（MMP/ADAM）の機能関節疾患での役割 (2012)
  • Author(s): 岡田保典
  • Organizer: 第33回日本炎症・再生医学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] メタロプロテアーゼによる組織内微小環境因子代謝と癌細胞の増殖・浸潤・転移 (2012)
  • Author(s): 岡田保典
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Invited
• [Book] Kelley's Textbook of Rheumatology. (2015)
  • Author(s): Okada Y.
  • Publisher: Elsevier Saunders.
• [Book] Handbook of Proteolytic Enzymes (2013)
  • Author(s): Mochizuki S. and Okada Y.
  • Publisher: Elsevier Ltd
• [Book] Kelley's Textbook of Rheumatology (2013)
  • Author(s): Okada Y.
  • Publisher: Elsevier Saunders
• [Book] Handbook of Proteolytic Enzymes. (2013)
  • Author(s): Mochizuki S. and Okada Y.
  • Publisher: Academic Press
• [Book] Kelley's Textbook of Rheumatology. (2013)
  • Author(s): Okada Y
  • Publisher: Elsevier Saunders
• [Remarks] 慶應義塾大学 岡田研究室
  • URL: http://keio-okada-lab.jp/
• [Remarks] 慶應義塾大学医学部岡田研究室
  • URL: http://keio-okada-lab.jp/
• [Remarks] 岡田研究室ホームページ
  • URL: http://keio-okada-lab.jp/
• [Remarks] 慶應義塾大学 グローバルCOEプログラム 幹細胞医学のための教育研究拠点 最終成果活動報告書
• [Patent(Industrial Property Rights)] 抗ヒト膜型ADAM28抗体 (2015)
  • Inventor(s): 宮越陽、古城周久、岡田保典、望月早月、下田将之
  • Industrial Property Rights Holder: 宮越陽、古城周久、岡田保典、望月早月、下田将之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-045244
  • Filing Date: 2015-03-06
• [Patent(Industrial Property Rights)] Human antibody aginast aggrecanase-type ADAMTS species for therapeutics of aggrecanase-related diseases (2014)
  • Inventor(s): 宮越陽、中村美紀子、古城周久、望月早月、岡田保典
  • Industrial Property Rights Holder: 宮越陽、中村美紀子、古城周久、望月早月、岡田保典
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-14
  • Overseas
• [Patent(Industrial Property Rights)] ANTI-ADAM28 ANTIBODIES FOR THERAPEUTICS FOR CARCINOMAS (2012)
  • Inventor(s): Yasunoti Okada 他5名
  • Industrial Property Rights Holder: Yasunoti Okada 他5名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-11-19
  • Overseas