Regulatory Mechanism of RANK Gene Expression during Osteoclastic Differentiation of Bone Marrow Macrophage/Monocyte Lineage

• Project/Area Number: 21590419
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kobe University
• Principal Investigator: KITAZAWA Riko 神戸大学, 大学院・医学研究科, 特命准教授 (00273780)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 破骨細胞 / RANK / 遺伝子プロモータ / 転写因子 / RANKL / 造血細胞

Research Abstract

Receptor activator of NF-kappaB(RANK) expressed on osteoclasts and their precursors is a receptor for RANK Ligand(RANKL). RANKL-RANK interaction induces genes essential for the differentiation of osteoclasts through the binding of NFATc1 to target gene promoters. We have cloned a 6-kb fragment containing the 5'-flanking region of the mouse RANK gene and have analyzed the binding elements such as PU. 1(-480), and MITF(-100). Here, we showed the regulatory mechanism of RANK gene transcription through the NFAT(-370) and CRE/AP-1 binding sites(-240). Furthermore, we have identified a novel alternative splicing variant of mouse RANK gene that contains a new intervening exon between exon 1 and exon 2 of mouse full-length RANK mRNA, and shown that variant RANK is a novel osteoclast suppressor that reduces the number of RANKL-induced mature osteoclasts mainly by negating the anti-apoptotic effect of RANKL.

Research Products

• [Journal Article] A. p D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse (2012)
  • Author(s): Kitazawa S, Kondo T, Mori K, Yokoyama N, Matsuo M, Kitazawa R.
  • Journal Title: Human Mutation Volume: (in press)
  • 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, Noda M
  • Journal Title: J Cell Physiol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting Osteoclastogenesis (2012)
  • Author(s): Wang Y, Liul W, Masuyama R, Fukuyama R, Ito M, Zhang Q, Komori H, Murakami T, Moriishi T, Miyazaki T, Kitazawa R, Yoshida CA, Kawai Y, Izumi S, Komori T
  • Journal Title: Bone Volume: 50 Pages: 409-419
  • Peer Reviewed
• [Journal Article] Identification and analysis of function of a novel splicing variant of mouse receptor activator of NF-kappaB (2011)
  • Author(s): Mukai S, Kitazawa R, Ishii J, Kondo T, Hakozaki A, Hosiuchi K, Kiyoshi M, Kitazawa S.
  • Journal Title: Mol Cell Biochem Volume: 350 Pages: 29-38
  • Peer Reviewed
• [Journal Article] Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β(TGF-β) Signaling in Cancer(review). Sann Sanda Khin (2011)
  • Author(s): Kitazawa R, Kondo T, Idei Y, Fujimoto M, Haraguchi R, Mori K, Kitazawa S
  • Journal Title: Cancers Volume: 3 Pages: 982-993
  • Peer Reviewed
• [Journal Article] Parathyroid hormone-responsive Smad3-related factor, Tmem119, promotes osteoblast differentiation and interacts with the bone morphogenetic protein-Runx2 pathway (2011)
  • Author(s): Hisa I, Inoue Y, Hendy GN, Canaff L, Kitazawa R, Kitazawa S, Komori T, Sugimoto T, Seino S, Kaji H
  • Journal Title: J Biol Chem Volume: 286 Pages: 9787-9796
  • Peer Reviewed
• [Journal Article] Chemerin regulates β-cell function in mice. (2011)
  • Author(s): Takahashi M, Okimura Y, Iguchi G, Nishizawa H, Yamamoto M, Suda K, Kitazawa R, Fujimoto W, Takahashi K, Zolotaryov FN, Hong KS, Kiyonari H, Abe T, Kaji H, Kitazawa S, Kasuga M, Chihara K, Takahashi Y.
  • Journal Title: Scientific Reports Volume: 1 Issue: 1 Pages: 123-123
  • DOI: 10.1038/srep00123
  • Peer Reviewed
• [Journal Article] Carvedilol ameliorates low-turnover bone disease in nonobese type 2 diabetes (2011)
  • Author(s): Goto S, Fujii H, Kono K, NakaiK, Hamada H, Yamato H, Shinohara M, Kitazawa R, Kitazawa S, Nishi S, Fukagawa M
  • Journal Title: Am J Nephrol Volume: 34 Pages: 281-290
  • Peer Reviewed
• [Journal Article] Carvedilol ameliorates low-turnover bone disease in non-obese type 2 diabetes (2011)
  • Author(s): Shunsuke Goto, Hideki Fujii, Keiji Kono, Kentaro Nakai, Yasuhiro Hamada, Hideyuki Yamato, Masami Shinohara, Riko Kitazawa, Sohei Kitazawa, Shinichi Nishi, and Masafumi Fukagaw
  • Journal Title: Am J Nephrol Volume: 34(3) Issue: 3 Pages: 281-290
  • DOI: 10.1159/000330853
  • Peer Reviewed
• [Journal Article] Pyruvate dehydrogenase kinase 4 induce bone loss at unloading by promoting Osteoclastogenesis (2011)
  • Author(s): Wang Y, Liul W, et al
  • Journal Title: Bone Volume: 50 Pages: 409-419
  • Peer Reviewed
• [Journal Article] Identification and analysis of function of a novel splicing variant of mouse receptor activator of□NF-kappaB (2011)
  • Author(s): S.Mukai, et al.
  • Journal Title: Molecular and Cellular Biochemistry Volume: (in press)
  • Peer Reviewed
• [Journal Article] Epigenetic alteration by DNA promoter hypermethylation of genes related to transforming growth factor-β (TGF-β) signaling. (2011)
  • Author(s): Sann Sanda Khin, et al.
  • Journal Title: Cancers Volume: 3 Pages: 982-993
  • Peer Reviewed
• [Journal Article] Depressed expression of Klotho and FGFR1 in hyperplastic parathyroid glands from uremic patients (2010)
  • Author(s): Komaba H, Goto S, Fujii H, Hamada Y, Kobayashi A, Shibuya K, Tominaga Y, Otsuki N, Nibu K, Kitazawa R, Fukagawa M
  • Journal Title: Kidney Int Volume: 77 Pages: 232-238
  • Peer Reviewed
• [Journal Article] Oxidative and nitrosative stress and progression of diabetic nephropathy in type 2 diabetes (2010)
  • Author(s): Fujii H, Kono K, Nakai K, Goto S, Komaba H, Hamada Y, Shinohara M, Kitazawa R, Kitazawa S, Fukagawa M
  • Journal Title: Am J Nephrol Volume: 31 Pages: 342-352
  • Peer Reviewed
• [Journal Article] Enhancement of ultraviolet B-induced skintumor development in phospholipase Cknockout mice is associated with decreased apoptosis (2010)
  • Author(s): Oka M, Edamatsu H, Kunisada M, Dien S, Kitazawa R, Kataoka T, Nishigori C
  • Journal Title: Carcinogenesis Volume: 31 Pages: 1897-1902
  • Peer Reviewed
• [Journal Article] The effect of the receptor for advanced glycation end products(RAGE) on bone metabolism under physiological and diabetic conditions (2010)
  • Author(s): Hamada Y, Kitazawa S, Kitazawa R, Kone K, Goto S, Komaba H, Fujii H, Yamamoto Y, Yamamoto H, Usami M, Fukagawa M
  • Journal Title: Endocr Volume: 38 Pages: 369-376
  • NAID: 120003338593
  • Peer Reviewed
• [Journal Article] Depressed expression of Klotho and FGFR1 in hyperplastic parathyroid glands from uremic patients. (2010)
  • Author(s): H.Komaba, et al.
  • Journal Title: Kidney International Volume: 77 Pages: 232-238
  • Peer Reviewed
• [Journal Article] BAMBI gene is epigenetically silenced in a subset of high-grade bladder cancer (2009)
  • Author(s): Sann Sanda Khin, Kitazawa R, Win N, Than TA, Mori K, Kondo T, Kitazawa S
  • Journal Title: Int J Cancer Volume: 125 Pages: 328-338
  • Peer Reviewed
• [Journal Article] Osteosarcoma in a pregnant patient with McCune-Albright syndrome (2009)
  • Author(s): Kanazawa I, Yamauchi M, Yano S. Imanishi Y, Kitazawa R, Nariai Y, Araki A, Kobayashi K, Inaba M, Maruyama R, Yamaguchi T, Sugimoto T
  • Journal Title: Bone Volume: 45 Pages: 603-609
  • Peer Reviewed
• [Journal Article] Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia (2009)
  • Author(s): Hamada Y, Fujii H, Kitazawa R, Yodoi J, Kitazawa S, Fukagawa M
  • Journal Title: Bone Volume: 44 Pages: 936-941
  • Peer Reviewed
• [Journal Article] Oral charcoal adsorbent(AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress (2009)
  • Author(s): Fujii H, Nishijima F, Goto S, Sugano M, Yamato H, Kitazawa R, Kitazawa S, Fukagawa M
  • Journal Title: Nephrol Dial Transplant Volume: 24 Pages: 2089-2095
  • Peer Reviewed
• [Journal Article] BAMBI gene is epigenetically silenced in a subset of high-grade bladder cancer (2009)
  • Author(s): Sann Sanda Khin, et al.
  • Journal Title: Int J Cancer 125 Pages: 328-338
  • Peer Reviewed
• [Journal Article] Ce promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis (2009)
  • Author(s): Li M., et al.
  • Journal Title: Carcinogenesis 30 Pages: 1424-1432
  • Peer Reviewed
• [Journal Article] Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia (2009)
  • Author(s): Hamada Y., et al.
  • Journal Title: Bone 44 Pages: 936-941
  • Peer Reviewed
• [Presentation] Analysis of Regulatory Mechanism of Mouse RANK Gene Expression through AP-1 Response Element (2011)
  • Author(s): Kitazawa R, Kinto S, et al
  • Organizer: ASBMR 2011 Annual Meeting
  • Place of Presentation: San Diego CA, USA
  • Year and Date: 2011-09-17
• [Presentation] AP-1応答配列を介するマウスRANK遺伝子発現制御機構の解析 (2011)
  • Author(s): 金籐聡美, 北澤理子, 他
  • Organizer: 第29回日本骨代謝学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2011-07-28
• [Presentation] 破骨細胞分化因子RANKLによる受容体RANKの発現制御機構 (2011)
  • Author(s): 北澤理子, 向井智美, 他
  • Organizer: 第100回日本病理学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-04-28
• [Presentation] 破骨細胞分化因子RANKLはNFATを介して受容体RANK発現を促進する (2010)
  • Author(s): 北澤理子, 他
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-04-28
• [Presentation] Analysis of Regulatory Mechanism of Mouse RANK Gene Expression through AP-1 Response Element (2010)
  • Author(s): Kitazawa R, Kinto S, Ishii J, Kondo T, Mori K, Kitazawa S
  • Organizer: ASBMR 2011 Annual Metting
  • Place of Presentation: San Diego, USA
• [Presentation] RANKL upregulates mouse RANK gene transcriptionthrough the NFAT binding site of RANK gene promoter (2010)
  • Author(s): Kitazawa R, Ishii J, Mukai S, Kondo T, Mori M, Mori K, Kitazawa S
  • Organizer: 第10回世界骨粗鬆症学会
  • Place of Presentation: フィレンツェ、イタリア
• [Presentation] Derepression of mouse SFRP-4 gene expression by oxidative stress : A plausible mechanism leading to low-turnover osteoporosis in diabetes and senescence (2010)
  • Author(s): Mori K, Kitazawa R, Kondo T, Mukai S, Mori M, Kitazawa S
  • Organizer: 第10回世界骨粗鬆症学会
  • Place of Presentation: フィレンツェ、イタリア
• [Presentation] Identification and functional analysis of a novel splicing variant of mouse RANK (2010)
  • Author(s): Mukai S, Kitazawa R, Ishii J, Kondo T, Hakozaki A, Horiuchi K, Mori K, Kitazawa S
  • Organizer: 第14回国際内分泌学会
  • Place of Presentation: 京都
• [Presentation] マウスRANK遺伝子転写におけるNFATの機能解析 (2009)
  • Author(s): 北澤理子, 他
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2009-05-03
• [Presentation] RANKL upregulates mouse RANK gene transcription through the NFAT binding site of its gene promoter (2009)
  • Author(s): Kitazawa R, Ishii J, Mukai S, Kondo T, Mori K, Kitazawa S
  • Organizer: ASBMR 31st Annual Metting
  • Place of Presentation: Denver, USA
• [Presentation] Oxidative DNA damage to methylated CpG located at five bases upstream of TATA-box restores suppressed sFRP-4 gene expression : proposal of a unique mechanism towards diabetic osteoporosis (2009)
  • Author(s): Mori K, Kitazawa R, Fukagawa M, Hamada Y, Kondo T, Kitazawa S
  • Organizer: ASBMR 31st Annual Metting
  • Place of Presentation: Denver, USA
• [Book] 病理と臨床29巻臨時増刊号「病理診断に役立つ分子生物学」第1部-4 DNAシークエンス (2011)
  • Author(s): 北澤荘平、森清、近藤武史、北澤理子
  • Publisher: 文光堂
• [Book] In situ detection of specific gene expression during and immediately after transcription at electron microscopic level. In Microscopy : Science, Technology, Applications and Education (2011)
  • Author(s): S.Kitazawa, et al
  • Total Pages: 200
  • Publisher: Formatex Research Center, Spain
• [Book] 組織細胞化学2010-組織細胞化学イメージングの基礎と最前線:生体内分子局在と機能を探る- (2010)
  • Author(s): 北澤荘平, 森清, 近藤武史, 北澤理子
  • Publisher: 日本組織細胞化学会編集
• [Book] DNA Methylation Research Trends, Epigenetic roles of CpG methylation at non-CpG-islands revealed by morphology-oriented epigenetic research
  • Author(s): Kitazawa S, Mori K, Kondo T, Fujimoto M, Kitazawa R
  • Publisher: Nova
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/patho2/index.html