薬理学講座 研究

本講座では、糖鎖による骨代謝制御機構解明に向けて研究を行っております。

糖鎖が神経変性疾患、癌、感染症、生活習慣病、免疫疾患などに深く関与していることは、多くの研究がなされ明らかになっております。しかし、骨代謝への関与については、まだほとんど解明されておりません。そこで、私たちは、この解明に向けて一丸となって取り組んでおります。

スフィンゴ糖脂質による骨代謝制御

外界からのシグナル伝達の授受の最前線である脂質二重層の細胞膜には、受容体の他にスフィンゴ糖脂質などが存在し、これらの糖脂質が様々な細胞の受容体の活性/不活性を調節していることが知られている。このことより、骨芽細胞や破骨細胞においても、スフィンゴ糖脂質が増殖・分化に重要な役割を果たす受容体の局在や、その活性化を制御することで、増殖・分化が調節されている可能性がある。

1. スフィンゴ糖脂質による骨形成制御

骨芽細胞では、a系列ガングリオシドGD1aおよびグロボ系糖脂質のGb4の発現が認められた。また、Gb4が欠損したGb3合成酵素遺伝子ノックアウトマウスでは、野生型マウスと比較して、骨形成の低下による骨量の減少が認められた。また、グルコシルセラミド合成酵素阻害剤の処理により、GD1aやGb4の発現が低下した骨芽細胞では、その増殖が抑制された。そのメカニズムの1つとして、マイクロアレイによる網羅的解析の結果、スフィンゴ糖脂質の発現が血管新生に関与するAngptl6を介して骨芽細胞増殖を制御していることを明らかにした。現在、骨芽細胞に発現しているスフィンゴ糖脂質と増殖・分化を制御する受容体の会合の有無や、局在の変化を検討している。

Int. J. Mol. Sci. 20, 4619 (2019)

2. スフィンゴ糖脂質による骨吸収制御

b系列ガングリオシドは、レプチンの分泌に重要な役割を果たしていることが知られており、これらの糖脂質の欠損により、脂肪細胞からのレプチン分泌が低下する。一方で、レプチンは交感神経系を介して、破骨細胞による骨吸収を促進させることが知られている。これらの知見は、これらの糖脂質が欠損したマウスでは、レプチンの分泌が減少し、骨吸収が抑制される可能性を示していた。その検証結果として、15週齢の野生型マウスとそのノックアウトマウスの骨量に有意な差は認めなかったが、40週齢のノックアウトマウスでは、加齢に伴う骨量の減少が野生型マウスと比較して、有意に抑制されていた。また、その抑制は、骨形成に及ぼす影響ではなく、破骨細胞の減少による骨吸収の低下に基づくことを示した。また、40週齢のノックアウトマウスでは、血清中のレプチン量が低下しており、b系列ガングリオシドの欠損による骨吸収の低下が、レプチンの低下による可能性が示唆され、現在検討中である。

総説

  • Furukawa K, Ohmi Y, Ohkawa Y, Bhuiyan R, Zhang P, Tajima O, Hashimoto N, Hamamura K, Furukawa K. New era of research on cancer-associated glycosphingolipids. Cancer Sci. 110 (5), 1544-1551 (2019)
  • 戸苅彰史, 浜村和紀. カテコラミンと骨代謝. 内分泌・糖尿病・代謝内科46 (6), 434-438 (2018)
  • Hamamura K*, Furukawa K*. Glycosylation is involved in malignant properties of cancer cells. Cancer Transl. Med. 3 (6), 209-213 (2017) *Corresponding author
  • 浜村和紀*, 古川鋼一, 戸苅彰史. 糖鎖修飾による癌の悪性形質制御機構. 口腔組織培養学会誌 25 (2), 9-17 (2016) *Corresponding author
  • Hamamura K*, Chen A, Uto Y, Yokota H. Potential therapeutic applications of salubrinal for skeletal diseases and beyond. J. Nat. Sci. 1 (8), e151 (2015) *Corresponding author
  • Furukawa K, Hamamura K, Ohkawa Y, Ohmi Y, Furukawa K. Disialyl gangliosides enhance tumor phenotypes with differential modalities. Glycoconj. J. 29 (8-9), 579-584 (2012)
  • Furukawa K, Ohkawa Y, Yamauchi Y, Hamamura K, Ohmi Y, Furukawa K. Fine tuning of cell signals by glycosylation. J. Biochem. 151 (6), 573-578 (2012)
  • 古川鋼一, 浜村和紀, 大川祐樹, 大海雄介, 古川圭子. 糖鎖修飾によるシグナル伝達の制御. 実験医学 増刊 30 (5), 771-776 (2012)
  • 古川鋼一, 浜村和紀, 大川祐樹, 古川圭子. 分子標的薬からみた我が国における創薬. 日本臨床 68 (10), 1797-1802 (2010)
  • Zhang P, Hamamura K, Yokota H, Malacinski GM. Potential applications of pulsating joint loading in sports medicine. Exerc. Sport Sci. Rev. 37 (1), 52-56 (2009)
  • Furukawa K, Hamamura K, Nakashima H, Furukawa K. Molecules in the signaling pathway activated by gangliosides can be targets of therapeutics for malignant melanomas. Proteomics 8 (16), 3312-3316 (2008)
  • Zhang P, Hamamura K, Yokota H. A brief review of bone adaptation to unloading. Genomics Proteomics Bioinformatics. 6 (1), 4-7 (2008)
  • 古川鋼一, 浜村和紀, 大川祐樹, 中島英行, 章青, 古川圭子. 癌細胞の形質を創出する細胞膜近傍の分子複合体. 蛋白質核酸酵素 53 (12), 1547-1551 (2008)
  • Furukawa K, Hamamura K, Aixinjueluo W, Furukawa K. Biosignals modulated by tumor-associated carbohydrate antigens: Novel targets for cancer therapy. Ann. N. Y. Acad. Sci. 1086, 185-198 (2006)

過去10年の主な原著論文

  • Yesmin F, Bhuiyan RH, Ohmi Y, Yamamoto S, Kaneko K, Ohkawa Y, Zhang P, Hamamura K, Cheung NV, Kotani N, Honke K, Okajima T, Kambe M, Tajima O, Furukawa K, Furukawa K. Ganglioside GD2 enhances the malignant phenotypes of melanoma cells by cooperating with integrins. Int. J. Mol. Sci. 23 (1), 423 (2022)
  • Mishima Y, Hamamura K*, Kato H, Furukawa K, Tashima Y, Okajima T, Kondo H, Sato T, Miyazawa K, Goto S, Togari A. Contribution of glucosylceramide synthase to the proliferation of mouse osteoblasts. In Vivo 35 (6), 3111-3123 (2021) *Corresponding author
  • Kimura F, Miyazawa K, Hamamura K, Tabuchi M, Sato T, Asano Y, Kako S, Aoki Y, Sugita Y, Maeda H, Togari A, Goto S. Suppression of alveolar bone resorption by salubrinal in a mouse model of periodontal disease. Life Sci. 284, 119938 (2021)
  • Muramatsu R, Sato T, Hamamura K, Miyazawa K, Takeguchi A, Tabuchi M, Togari A, Goto S. Guanabenz inhibits alveolar bone resorption in a rat model of periodontitis. J. Pharmacol. Sci. 147 (3), 294-304 (2021)
  • Hotta H, Hamamura K*, Shibuya H, Ohmi Y, Furukawa K, Furukawa K. Lewis y expressed in oral squamous cell carcinoma attenuates malignant properties via down-regulation of EGF signaling. Anticancer Res. 41 (4), 1821-1830 (2021) *Corresponding author
  • Kusafuka S, Kondo H, Hayashi K, Hamamura K, Sato T, Miyazawa K, Goto S, Togari A. Effects of glucocorticoids on diurnal variations in experimental tooth movement. J. Hard Tissue Biol. 29 (4), 231-238 (2020)
  • Hamamura K*, Hotta H, Murakumo Y, Shibuya H, Kondo Y, Furukawa K. SSEA-3 and 4 are not essential for the induction or properties of mouse iPS cells. J. Oral Sci. 62 (4), 393-396 (2020) *Corresponding author
  • Li J, Li X, Liu D, Hamamura K, Wan Q, Na S, Yokota H, Zhang P. eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice. Cell Death Dis. 10 (12), 921 (2019)
  • Hamamura K*, Hamajima K, Yo S, Mishima Y, Furukawa K, Uchikawa M, Kondo Y, Mori H, Kondo H, Tanaka K, Miyazawa K, Goto S, Togari A. Deletion of Gb3 synthase in mice resulted in the attenuation of bone formation via decrease in osteoblasts. Int. J. Mol. Sci. 20 (18), 4619 (2019) *Corresponding author
  • Yo S, Hamamura K*, Mishima Y, Hamajima K, Mori H, Furukawa K, Kondo H, Tanaka K, Sato T, Miyazawa K, Goto S, Togari A. Deficiency of GD3 synthase in mice resulting in the attenuation of bone loss with aging. Int. J. Mol. Sci. 20 (11), 2825 (2019) *Corresponding author
  • Tanaka K, Kondo H, Hamamura K, Togari A. Systemic administration of low-dose naltrexone increases bone mass due to blockade of opioid growth factor receptor signaling in mice osteoblasts. Life Sci. 224, 232-240 (2019)
  • Hayashi K, Kondo H, Kusafuka S, Tanaka K, Hamamura K, Hirai T, Sato T, Miyazawa K, Goto S, Togari A. Alpha 1B-adrenergic receptor signaling contributes to experimental tooth movement. Aichi Gakuin Dent. Sci. 31, 31-41 (2018)
  • Ohmi Y, Kambe M, Ohkawa Y, Hamamura K, Tajima O, Takeuchi R, Furukawa K, Furukawa K. Differential roles of gangliosides in malignant properties of melanomas. PLoS ONE 13 (11), e0206881 (2018)
  • Hamajima K, Hamamura K*, Chen A, Yokota H, Mori H, Yo S, Kondo H, Tanaka K, Ishizuka K, Kodama D, Hirai T, Miyazawa K, Goto S, Togari A. Suppression of osteoclastogenesis via α2-adrenergic receptors. Biomed. Rep. 8 (5), 407-416 (2018) *Corresponding author
  • Mori H, Hamamura K*, Yo S, Hamajima K, Ootani K, Honda M, Ishizuka K, Kondo H, Tanaka K, Kodama D, Hirai T, Miyazawa K, Goto S, Togari A. Conditioned medium from rat dental pulp reduces the number of osteoclasts via attenuation of adhesiveness in osteoclast precursors. J. Oral Sci. 60 (3), 352-359 (2018) *Corresponding author
  • Chen A, Wang L, Li BY, Sherman J, Ryu JE, Hamamura K, Liu Y, Nakshatri H, Yokota H. Reduction in migratory phenotype in a metastasized breast cancer cell line via downregulation of S100A4 and GRM3. Sci. Rep. 7 (1), 3459 (2017)
  • Kodama D, Hirai T, Kondo H, Hamamura K, Togari A. Bidirectional communication between sensory neurons and osteoblasts in an in vitro co-culture system. FEBS Lett. 591 (3), 527-539 (2017)
  • Tanaka K, Hirai T, Kodama D, Kondo H, Hamamura K, Togari A. Pharmacological blockade of 5-HT2B receptor signaling impairs bone formation in mice. Aichi Gakuin Dent. Sci. 29, 1-7 (2016)
  • Hamamura K*, Tanjung N, Chen A, Yokota H, Togari A. Suppression of osteoclastogenesis via upregulation of Zfyve21 and Ddit4 by salubrinal and guanabenz. Oral Therap. Pharmacol. 35 (3), 127-135 (2016) *Corresponding author
  • Takigawa S, Frondorf B, Liu S, Liu Y, Li B, Sudo A, Wallace JM, Yokota H, Hamamura K*. Salubrinal improves mechanical properties of the femur in osteogenesis imperfecta mice. J. Pharmacol. Sci. 132 (2), 154-161 (2016) *Corresponding author
  • Takigawa S, Chen A, Nishimura A, Liu S, Li BY, Sudo A, Yokota H, Hamamura K*. Guanabenz downregulates inflammatory responses via eIF2α dependent and independent signaling. Int. J. Mol. Sci. 17 (5), 674 (2016) *Corresponding author
  • Makino Y, Hamamura K, Takei Y, Bhuiyan RH, Ohkawa Y, Ohmi Y, Nakashima H, Furukawa K, Furukawa K. A therapeutic trial of human melanomas with combined small interfering RNAs targeting adaptor molecules p130Cas and paxillin activated under expression of ganglioside GD3. Biochim. Biophys. Acta Gen. Subj. 1860 (8), 1753-1763 (2016)
  • Takigawa S, Chen A, Wan Q, Na S, Sudo A, Yokota H, Hamamura K*. Role of miR-222-3p in c-Src-mediated regulation of osteoclastogenesis. Int. J. Mol. Sci. 17 (2), 240 (2016) *Corresponding author
  • Tanaka K, Hirai T, Kodama D, Kondo H, Hamamura K, Togari A. α1B-Adrenoceptor signalling regulates bone formation through the up-regulation of CCAAT/enhancer-binding protein δ expression in osteoblasts. Br. J. Pharmacol. 173 (6), 1058-1069 (2016)
  • Tanaka K, Hirai T, Kodama D, Kondo H, Hamamura K, Togari A. α1B-Adrenoceptor signalling regulates bone formation through the up-regulation of CCAAT/enhancer-binding protein δ expression in osteoblasts. Br. J. Pharmacol. 173 (6), 1058-1069 (2016)
  • Liu S, Liu D, Chen C, Hamamura K, Moshaverinia A, Yang R, Liu Y, Jin Y, Shi S. MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in Lupus. Cell Metab. 22 (4), 606-618 (2015)
  • Xu W, Wan Q, Na S, Yokota H, Yan JL*, Hamamura K*. Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13. Cell. Signal. 27 (12), 2332-2342 (2015) *Corresponding author
  • Hamamura K*, Nishimura A, Iino T, Takigawa S, Sudo A, Yokota H. Chondroprotective effects of salubrinal in a mouse model of osteoarthritis. Bone Joint Res. 4 (5), 84-92 (2015) *Corresponding author
  • Hamamura K*, Nishimura A, Chen A, Takigawa S, Sudo A, Yokota H. Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis. Cell. Signal. 27 (4), 828-835 (2015) *Corresponding author
  • Hamamura K*, Chen A, Tanjung N, Takigawa S, Sudo A, Yokota H. In vitro and in silico analysis of an inhibitory mechanism of osteoclastogenesis by salubrinal and guanabenz. Cell. Signal. 27 (2), 353-362 (2015) *Corresponding author
  • Hamamura K*, Chen A, Nishimura A, Tanjung N, Sudo A, Yokota H. Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis. Cell. Signal. 26 (11), 2358-2369 (2014) *Corresponding author
  • Hamamura K*, Minami K, Tanjung N, Wan Q, Koizumi M, Matsuura N, Na S, Yokota H. Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling. Int. J. Oncol. 44 (6), 1980-1988 (2014) *Corresponding author
  • Hamamura K*, Chen A, Tanjung N, Sun HB, Yokota H. In Vitro and in Silico analysis of ADAMTS5 transcription in human chondrocytes. J. Arthritis 2 (1), 111 (2013) *Corresponding author
  • Hamamura K, Zhang P, Zhao L, Shim JW, Chen A, Dodge TR, Wan Q, Shih H, Na S, Lin CC, Sun HB, Yokota H. Knee loading reduces MMP13 activity in the mouse cartilage. BMC Musculoskelet. Disord. 14 (1), 312 (2013)
  • Yokota H, Hamamura K, Chen A, Dodge TR, Tanjung N, Abedinpoor A, Zhang P. Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells. BMC Musculoskelet. Disord. 14 (1), 197 (2013)
  • Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tsuchida A, Okajima T, Furukawa K, Urano T, Furukawa K. Trimeric Tn antigen on Syndecan-1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin α5β1 and matrix metalloproteinase 9. J. Biol. Chem. 288 (33), 24264-24276 (2013)
  • Shim JW, Hamamura K, Chen A, Wan Q, Na S, Yokota H. Rac1 mediates load-driven attenuation of mRNA expression of nerve growth factor beta in cartilage and chondrocytes. J Musculoskelet. Neuronal. Interact. 13 (3), 372-379 (2013)
  • Hamamura K*, Tanjung N, Yokota H. Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha. J. Bone Miner. Metab. 31 (6), 618-628 (2013) *Corresponding author
  • Hamamura K, Lin CC, Yokota H. Salubrinal reduces expression and activity of MMP13 in chondrocytes. Osteoarthritis Cartilage 21 (5), 764-772 (2013)
  • Hotta H, Hamamura K, Yamashita K, Shibuya H, Tokuda N, Hashimoto N, Furukawa K, Yamamoto N, Hattori H, Toyokuni S, Ueda M, Furukawa K. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x. Glycoconj. J. 30 (6), 585-597 (2013)
  • Hashimoto N, Hamamura K, Kotani N, Furukawa K, Kaneko K, Honke K, Furukawa K. Proteomic analysis of ganglioside-associated membrane molecules: Substantial basis for molecular clustering. Proteomics 12 (21), 3154-3163 (2012)
  • Shibuya H, Hamamura K, Hotta H, Matsumoto Y, Nishida Y, Hattori H, Furukawa K, Ueda M, Furukawa K. Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci. 103 (9), 1656-1664 (2012)
  • Hamamura K, Swarnkar G, Tanjung N, Cho E, Li J, Na S, Yokota H. RhoA-mediated signaling in mechanotransduction of osteoblasts. Connect. Tissue Res. 53 (5), 398-406 (2012)
  • Hamamura K, Zhao L, Jiang C, Tanjung N, Swarnkar G, Yokota H. Hydroxyapatite modulates mRNA expression profiles in cultured osteocytes. Cell. Mol. Bioeng. 5(2), 217-226 (2012)
  • Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tokuda N, Tsuchida A, Matsubara T, Hori T, Okajima T, Furukawa K, Urano T, Furukawa K. pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen. Biochem. Biophys. Res. Commun. 419 (1), 7-13 (2012)
  • Yamauchi Y, Furukawa K, Hamamura K, Furukawa K. Positive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling: Induction of the lipogenic pathway by a melanoma antigen. Cancer Res. 71 (14) 4989-4997 (2011)
  • Hamamura K, Tsuji M, Hotta H, Ohkawa Y, Takahashi M, Shibuya H, Nakashima H, Yamauchi Y, Hashimoto N, Hattori H, Ueda M, Furukawa K, Furukawa K. Functional activation of Src family kinase yes protein is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3. J. Biol. Chem. 286 (21) 18526-18537 (2011)