Locomotive syndrome of musculoskeletal system will lead to limitation of the patient function in activity of daily living (ADL). Our standard approach to treat the patients includes medication, non-surgical and surgical treatment, however it is possible to prevent onset or progression of certain disease if we could reveal pathogenesis of the disease. Using recent technology in molecular science, we have been investigating pathogenesis and mechanism of onset of number of diseases in musculoskeletal system, such as osteoporosis, rheumatoid arthritis, sarcopenia, ossification of the posterior longitudinal ligament of the spine, and aseptic necrosis of the femoral neck.
Takeshi Miyamoto, MD
A novel molecule to induce cell-cell fusion of the osteoclast (DC-STAMP)
The osteoclast, which is giant cell and has dominant role in bone resorption, is created by cell-cell fusion, but no one has ever found a key molecule to induce the cell-cell fusion. We have determined the key molecule, DC-STAMP, which induces cell-cell fusion and is essential to create the osteoclast. There was osteoclast formation in wild type mice (left) but no osteoclast formation in DC-STAMP knock-out mice (right).
A second molecule to induce cell-cell fusion of the osteoclast
We have determined the second key molecule, OC-STAMP, which induces cell-cell fusion and is essential to create the osteoclast. There was osteoclast formation in wild type mice (left) but no osteoclast formation in OC-STAMP knock-out mice (right).
A novel pathway to control the osteoclast differentiation
There is a positive pathway to control the osteoclast differentiation by activation of several factors such as NFATc1 based on RANKL stimulation. We have found a negative pathway to control the osteoclast differentiation by Blimp1-Bcl6, and its essential role.
A molecular target of the rheumatoid arthritis
Rheumatoid arthritis leads to chronic and systemic inflammation of the synovial joints. We have determined a key molecule, STAT3, which can be a treatment target molecule. Joint destruction was observer in untreated model (left), however the joint cartilage was preserved in the treated model by the STAT3 inhibitor.
Mutation of aldehyde dehydrogenase 2 (ALDH2) can be a risk to cause osteoporosis
Almost half of Japanese population have mutation in the aldehyde dehydrogenase 2 (ALDH2), and it limits capacity of alcohol resorption in the human body. We have found that mutation in the ALDH2 resulted in decrease of bone mineral density in the mice model
Fujie A, Funayama A, Miyauchi Y, Sato Y, Kobayashi T, Kanagawa H, Katsuyama E, Hao W, Tando T, Watanabe R, Morita M, Miyamoto K, Kanaji A, Morioka H, Matsumoto M, Toyama Y and Miyamoto T. Bcl6 promotes osteoblastogenesis through Stat1 inhibition. Biochem Biophys Res Commun. In press. (2.281)
Kanagawa H, Niki Y, Kobayashi T, Sato Y, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Watanabe R, Morita M, Morioka H, Matsumoto M, Toyama Y, Miyamoto T. Mycobacterium tuberculosis promotes arthritis development through toll-like receptor 2. J Bone Miner Metab. in press. (2.114)
Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, Fujie A, Tando T, Watanabe R, Morita M, Miyamoto K, Niki Y, Morioka H, Matsumoto M, Toyama Y, Miyamoto T. Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. J Biol Chem. 290, 2, 716-26, 2015 Jan. (4.600)
Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T, Mukouyama YS, Sato TN, Suda T, Ema M, Kubota Y. Cell. Neurons limit angiogenesis by titrating VEGF in retina. Cell. 159, 3, 584-96, 2014 Oct. (33.116)
Sato Y, Miyauchi Y, Yoshida S, Morita M, Kobayashi T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Miyamoto T. The Vitamin D Analogue ED71 but Not 1,25(OH) 2D3 Targets HIF1α Protein in Osteoclasts. PLoS One. 9, 11, e111845, 2014 Nov. (3.534)
Fujita N, Hirose Y, Tran CM, Chiba K, Miyamoto T, Toyama Y, Shapiro IM, Risbud MV. HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB J. 28, 6, 2455-65, 2014 Jun. (5.480)
Mori T, Sato Y, Miyamoto K, Kobayashi T, Shimizu T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Iwasaki R, Kawana H, Morioka H, Matsumoto M, Saya H, Toyama Y, Miyamoto T. TNFa promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. Oncogene. 33, 33, 4236-41, 2014 Aug. (8.559)
Odagiri H, Kadomatsu T, Endo M, Masuda T, Morioka MS, Fukuhara S, Miyamoto T, Kobayashi E, Miyata K, Aoi J, Horiguchi H, Nishimura N, Terada K, Yakushiji T, Manabe I, Mochizuki N, Mizuta H, Oike Y. The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases. Sci Signal.7, 309, ra7, 2014 Jan. (6.337)
Takeshi Miyamoto. Role of osteoclasts in regulating hematopoietic stem and progenitor cells. World journal of Orthopaedics. 4, 3, 2013 July 18.
Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Morioka H, Matsumoto M, Chambon P, Johnson RS, Kato S, Toyama Y and Miyamoto T. HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc Natl Acad Sci U S A. in press. (9.737)
Mirza R, Qiao S, Tateyama K, Miyamoto T, Xiuli L, Seo H. 3β-Hydroxysterol-Delta24 reductase plays an important role in long bone growth by protecting chondrocytes from reactive oxygen species. J Bone Miner Metab. 30, 2, 144-53, 2012 Mar. (2.238)
Miyamoto H, Suzuki T, Miyauchi Y, Iwasaki R, Kobayashi T, Sato Y, Miyamoto K, Hoshi H, Hashimoto K, Yoshida S, Hao W, Mori T, Kanagawa H, Katsuyama E, Fujie A, Morioka H, Matsumoto M, Chiba K, Takeya M, Toyama Y, Miyamoto T. Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells. J Bone Miner Res. 27, 6, 1289-97, 2012 Jun. (7.059)
Fujita K, Iwasaki M, Ochi H, Fukuda T, Ma C, Miyamoto T, Takitani K, Negishi-Koga T, Sunamura S, Kodama T, Takayanagi H, Tamai H, Kato S, Arai H, Shinomiya K, Itoh H, Okawa A, Takeda S. Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat Med. 18, 4, 589-94, 2012 Mar. (25.430 )
Yoshida S, Iwasaki R, Kawana H, Miyauchi Y, Hoshi H, Miyamoto H, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Kobayashi T, Sato Y, Miyamoto K, Morioka H, Matsumoto M, Chiba K, Toyama Y, Nakagawa T, Miyamoto T. PDGFBB promotes PDGFRα-positive cell migration into artificial bone in vivo. Biochem Biophys Res Commun. 421, 4, 785-9, 2012 May. (2.595)
Hoshi H, Hao W, Fujita Y, Funayama A, Miyauchi Y, Hashimoto K, Miyamoto K, Iwasaki R, Sato Y, Kobayashi T, Miyamoto H, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Kitagawa K, Nakayama KI, Kawamoto T, Sano M, Fukuda K, Ohsawa I, Ohta S, Morioka H, Matsumoto M, Chiba K, Toyama Y, Miyamoto T. Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. J Bone Miner Res. 27, 9, 2015-23, 2012 Sep. (7.059)
Miyauchi Y, Miyamoto H, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Hoshi H, Miyamoto K, Sato Y, Kobayashi T, Akiyama H, Morioka H, Matsumoto M, Toyama Y, Miyamoto T. Conditional inactivation of Blimp1 in adult mice promotes increased bone mass. J Biol Chem. 287, 34, 28508-17, 2012 Aug . (4.773)
Miyamoto H, Katsuyama E, Miyauchi Y, Hoshi H, Miyamoto K, Sato Y, Kobayashi T, Iwasaki R, Yoshida S, Mori T, Kanagawa H, Fujie A, Hao W, Morioka H, Matsumoto M, Toyama Y, Miyamoto T. An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion. J Biol Chem. 287, 39, 32479-84, 2012 Sep. (4.773)
Iriuchishima H, Takubo K, Miyakawa Y, Nakamura-Ishizu A, Miyauchi Y, Fujita N, Miyamoto K, Miyamoto T, Ikeda E, Kizaki M, Nojima Y, Suda T. Neovascular niche for human myeloma cells in immunodeficient mouse bone. PLoS One. 7, 2, e30557, 2012. (4.411)
Shimizu T, Ishikawa T, Iwai S, Ueki A, Sugihara E, Onishi N, Kuninaka S, Miyamoto T, Toyama Y, Ijiri H, Mori H, Matsuzaki Y, Yaguchi T, Nishio H, Kawakami Y, Ikeda Y, Saya H. Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma. Mol Cancer Res. 10, 3, 454-68, 2012 Mar. (4.373)
Niki Y, Takeuchi T, Nakayama M, Nagasawa H, Kurasawa T, Yamada H, Toyama Y, Miyamoto T. . Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy. PLoS One. 7, 5, e37447, 2012. (4.092)
Nakayama M, Niki Y, Kawasaki T, Takeda Y, Horiuchi K, Sasaki A, Okada Y, Umezawa K, Ikegami H, Toyama Y, Miyamoto T. Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha. Arthritis Res Ther. 14, 3, R120, 2012 May. (4.445)
Hosogane N, Watanabe K, Tsuji T, Miyamoto T, Ishii K, Niki Y, Nakamura M, Toyama Y, Chiba K, Matsumoto M. Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis. J Orthop Res. 30, 8, 1249-53, 2012 Aug. (2.976)
