Elucidation of molecular mechanism of the regulation of skeletal homeostasis, and development of new therapeutic approaches against skeletal disorders

• Project/Area Number: 25293215
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Toshio 徳島大学, 藤井節郎記念医科学センター, 副理事 (20157374)
• Co-Investigator(Kenkyū-buntansha): FUKUMOTO Seiji 徳島大学, 藤井節郎記念医科学センター, 特任教授 (30202287) ; ABE Masahiro 徳島大学, 大学院医歯薬学研究部, 教授 (80263812) ; 遠藤 逸朗 徳島大学, 大学病院, 講師 (10432759) ; 粟飯原 賢一 徳島大学, ヘルスバイオサイエンス研究部, 講師 (70372711)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: インターロイキン-11 (IL-11) / Wntシグナル / 骨芽細胞 / 脂肪細胞 / 骨髄腫 / 破骨細胞 / Pim-2 / 遺伝子 / シグナル伝達 / 脂質 / 老化

Outline of Final Research Achievements

IL-11 regulates osteoblast/adipocyte differentiation via Wnt signaling. In order to clarify the role of IL-11 on the regulation of osteogenesis and adipogenesis, we created IL-11 knockout mice. These mice exhibited reduced bone mass due to suppressed bone formation, along with increased adipose tissue mass with insulin resistance and glucose intolerance. These results demonstrate the important role of IL-11 in the regulation of osteoblast/adipocyte differentiation.
Interaction of myeloma cells with bone cells enhanced Pim-2 expression in myeloma cells, and Pim-2 enhanced survival and drug resistance of myeloma cells. Myeloma cell-osteoblast interaction also enhanced Pim-2 expression in osteoblasts, which suppressed osteoblast differentiation. Furthermore, Pim inhibitors potently suppressed myeloma growth and enhanced bone formation. These observations suggest that inhibition of Pim-2 may become a new therapeutic approach against multiple myeloma.

Research Products

• [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. (2015)
  • Author(s): Hiasa M, Teramachi J, Oda A, Amachi R, Harada T, Nakamura S, Miki H, Fujii S, Kagawa K, Watanabe K, Endo I, Kuroda Y, Yoneda T, Tsuji D, Nakao M, Tanaka E, Hamada K, Sano S, Itoh K, Matsumoto T, Abe M.
  • Journal Title: Leukemia Volume: 29 Pages: 207-217
  • Peer Reviewed
• [Journal Article] Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation. (2015)
  • Author(s): Hanson DJ, Nakamura S, Amachi R, Hiasa M, Oda A, Tsuji D, Itoh K, Harada T, Horikawa K, Teramachi J, Miki H, Matsumoto T, Abe M.
  • Journal Title: Oncotarget Volume: 6 Pages: 33568-33586
  • Peer Reviewed
• [Journal Article] Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH). (2015)
  • Author(s): Dong B, Endo I, Ohnishi Y, Kondo T, Hasegawa T, Amizuka N, Kiyonari H, Shioi G, Abe M, Fukumoto S, Matsumoto T.
  • Journal Title: J Bone Miner Res Volume: 30 Pages: 1980-1993
  • Peer Reviewed
• [Journal Article] The Effect of Discontinuing Treatment With Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density. (2015)
  • Author(s): ecknor CP, Recker RR, Benson CT, Robins DA, Chiang AY, Alam J, Hu L, Matsumoto T, Sowa H, Sloan JH, Konrad RJ, Mitlak BH, Sipos AA.
  • Journal Title: J Bone Miner Res Volume: 30 Pages: 1717-1725
  • Peer Reviewed
• [Journal Article] A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. (2015)
  • Author(s): Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL.
  • Journal Title: J Bone Miner Res Volume: 30 Pages: 216-224
  • Peer Reviewed
• [Journal Article] Eldecalcitol reduces osteoporotic fractures by unique mechanisms. (2015)
  • Author(s): Kondo S, Takano T, Ono Y, Saito H, Matsumoto T
  • Journal Title: J Steroid Biochem Mol Biol Volume: 148 Pages: 232-238
  • Peer Reviewed / Open Access
• [Journal Article] The Effect of Discontinuing Treatment with Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women with Low Bone Mineral Density. (2015)
  • Author(s): Recknor CP, Recker RR, Benson CT, Robins DA, Chiang AY, Alam J, Hu L, Matsumoto T, Sowa H, Sloan JH, Konrad RJ, Mitlak BH, Sipos AA
  • Journal Title: J Bone Miner Res Volume: E-pub Feb 24
  • Peer Reviewed / Open Access
• [Journal Article] Defining and targeting myeloma stem cell-like cells. (2014)
  • Author(s): Abe M, Harada T, Matsumoto T
  • Journal Title: Stem Cells Volume: 32 Pages: 1067-1073
  • Peer Reviewed / Open Access
• [Journal Article] Magnetically responsive smart nanoparticles for cancer treatment with a combination of magnetic hyperthermia and remote-control drug release. (2014)
  • Author(s): Hayashi K, Nakamura M, Miki H, Ozaki S, Abe M, Matsumoto T, Sakamoto W, Yogo T, Ishimura K
  • Journal Title: Theranostics Volume: 4 Pages: 834-844
  • Peer Reviewed / Open Access
• [Journal Article] Vitamin D analogs and bone: preclinical and clinical studies with eldecalctol. (2014)
  • Author(s): Matsumoto-T, Takano T, Saito H, Takahashi F
  • Journal Title: BoneKEy Reports Volume: 3 Pages: 513-513
  • Peer Reviewed / Open Access
• [Journal Article] Fracture Risk Reduction with Denosumab in Japanese Postmenopausal Women and Men with Osteoporosis: Denosumab fracture Intervention RandomizEd placebo Controlled Trial (DIRECT). (2014)
  • Author(s): Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Shiraki M, Fukunaga M
  • Journal Title: J Clin Endocrinol Metab Volume: 99 Pages: 2599-2607
  • Peer Reviewed / Open Access
• [Journal Article] Relationship Between The Effect Of Eldecalcitol And Serum 25(OH)D Level. (2014)
  • Author(s): Takano T, Kondo S, Saito H, Matsumoto T
  • Journal Title: J Steroid Biochem Mol Biol Volume: 144 Pages: 124-127
  • Peer Reviewed / Open Access
• [Journal Article] High serum parathyroid hormone and calcium are risk factors for hypertension in Japanese patients. (2014)
  • Author(s): Yagi S, Aihara K, Kondo T, Endo I, Hotchi J, Ise T, Iwase T, Akaike M, Matsumoto T, Sata M
  • Journal Title: Endocr J Volume: 61 Pages: 727-733
  • NAID: 130004443979
  • Peer Reviewed / Open Access
• [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. (2014)
  • Author(s): Hiasa M, Jumpei T, Oda A, Amachi R, Harada T, Nakamura S, Miki S, Fujii S, Kagawa K, Watanabe K, Endo I, Kuroda Y, Yoneda T, Tsuji D, Nakao M, Tanaka E, Hamada K, Sano S, Itoh K, Matsumoto T, Abe M.
  • Journal Title: Leukemia Volume: in press
  • Peer Reviewed
• [Journal Article] Concise review: defining and targeting myeloma stem cell-like cells. (2014)
  • Author(s): Abe M, Harada T, Matsumoto T
  • Journal Title: Stem cells (Dayton, Ohio) Volume: 32 Pages: 1067-1073
  • Peer Reviewed
• [Journal Article] Parathyroid hormone (1-34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess. (2013)
  • Author(s): Kuriwaka-Kido R, Kido S, Miyatani Y, Ito Y, Kondo T, Omatsu T, Dong B, Endo I, Miyamoto K, Matsumoto T
  • Journal Title: Endocrinology Volume: 154 Pages: 1156-1167
  • Peer Reviewed
• [Journal Article] Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma. (2013)
  • Author(s): Harada T, Ozaki S, Oda A, Fujii S, Nakamura S, Miki H, Kagawa K, Takeuchi K, Matsumoto T, Abe M.
  • Journal Title: Int J Hematol Volume: 97(6) Pages: 743-748
  • NAID: 10031183730
  • Peer Reviewed
• [Journal Article] Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib. (2013)
  • Author(s): Nakamura S, Miki H, Kido S, Nakano A, Hiasa M, Oda A, Amou H, Watanabe K, Harada T, Fujii S, Takeuchi K, Kagawa K, Ozaki S, Matsumoto T, Abe M.
  • Journal Title: Int J Hematol. Volume: 98 Pages: 66-73
  • NAID: 10031189598
  • Peer Reviewed
• [Journal Article] Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors. (2013)
  • Author(s): Harada T, Ozaki S, Oda A, Tsuji D, Ikegame A, Iwasa M, Udaka K, Fujii S, Nakamura S, Miki H, Kagawa K, Kuroda Y, Kawai S, Itoh K, Yamada-Okabe H, Matsumoto T, Abe M.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Presentation] Pivotal role of TAK-1 in tumor growth and bone destruction in myeloma: therapeutic impact of TAK-1 inhibition. (2015)
  • Author(s): umpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe.
  • Organizer: Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Seattle, WA. (USA)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] RAIL is not a proapoptotic but rather anti-apoptotic mediator for osteoclasts to stimulate their differentiation and survival. (2015)
  • Author(s): Hirohfumi Tenshin, Jumpei Teramachi, Asuka Oda, Ryota Amachi, Masahiro Hiasa, Keiishiro Watanabe, Singen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe.
  • Organizer: Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Seattle, WA. (USA)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Spaceflight Bone Atrophy-Problem Solved? (2015)
  • Author(s): Adrian LeBlanc, Toshio Matsumoto, Jeffrey Jones, Jay Shapiro, Thomas Lang, Linda Shackelford, Scott M. Smith, Harlan Evans, Elisabeth Spector, Robert Ploutz-Snyder, Jean Sibonga, Joyce Keyak, Toshitaka Nakamura, Kenjiro Kohri, Hiroshi Ohshima, Gilbert Moralez.
  • Organizer: Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Seattle, WA. (USA)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Bisphosphonate ISS Flight Experiment. (2014)
  • Author(s): LeBlanc A, Matsumoto T, Jones J, Shapiro J, Lang T, Shackelford L, Smith SM, Evans H, Spector E, Ploutz-Snyder R, Sibonga J, Keyak J, Nakamura T, Kohri K, Ohshima H, Moralez G
  • Organizer: American Society of Bone and Mineral Research
  • Place of Presentation: Houston (USA)
  • Year and Date: 2014-09-12 – 2014-09-15
  • Invited
• [Presentation] Interleukin-11 is an important factor for mechanical stress-induced osteoblast differentiation and bone formation. (2014)
  • Author(s): Takeshi Kondo, Bingzi Dong, Takashi Omatsu, Yukiyo Ohnishi, Itsuro Endo, Masahiro Abe, Shinichi Aizawa, Hiroshi Sakaue, Toshio Matsumoto
  • Organizer: American Society of Bone and Mineral Research
  • Place of Presentation: Houston (USA)
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Effect of a calcilytic compound in autosomal dominant hypocalcemia model mice. (2014)
  • Author(s): Bingzi Dong, Itsuro Endo, Takeshi Kondo, Yukiyo Ohnishi, Masahiro Abe, Seiji Fukumoto, Tomoka Hasegawa, Norio Amizuka, Shin-ichi Aizawa, Toshio Matsumoto
  • Organizer: American Society of Bone and Mineral Research
  • Place of Presentation: Houston (USA)
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Overview of the pathophysiology of MBD and acquired genetic events:Bench work for the targeted therapy to the microenvironment of MBD. Session: Myeloma bone disease.
  • Author(s): M Abe.
  • Organizer: The 14th International Myeloma Workshop.
  • Place of Presentation: Kyoto International Conference Center（ Kyoto, Japan）
  • Invited
• [Presentation] 骨髄腫骨病変と腫瘍免疫．シンポジウム5 骨免疫と炎症性疾患．
  • Author(s): 安倍正博
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 国立京都国際会館（京都府）
  • Invited
• [Presentation] Potent induction of bone formation in myeloma bone lesions by the cathepsin K inhibitor KK1-300-01 in combination with the proteasome inhibitor bortezomib.
  • Author(s): Keiichiro Watanabe, Masahiro Abe, Hiroshi Mori, Ryota Amachi, Masahiro Hiasa, Takeshi Harada, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto.
  • Organizer: 35th Annual Meeting, the American Society for Bone and Mineral Research, Baltimore
  • Place of Presentation: Baltimore Convention Center（Baltimore, Maryland, USA）