An integrated analyses on the implication of structural and promoter polymorphism of osteopontin modification

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Ehime University
• Principal Investigator: MIYAZAKI Tatsuhiko Ehime University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 助教授 (80239384)
• Co-Investigator(Kenkyū-buntansha): NOSE Masato Ehime University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (70030913) ; KAMEDA Kenji Ehime University, Integrated Center for Sciences, Lecturer, 総合科学研究支援センター, 講師 (60363264)
• Project Period (FY): 2005 – 2006
• Keywords: Osteopontin / Structural polymorphism / Promoter polymorphism / Congenic mice / Cell free protein synthesis

Research Abstract

We previously identified Opn as a candidate gene susceptible to glomerulonephritis in MRL/lpr mice by genome wide screening using (MRL/lpr x C3H/lpr)F_2 mice, followed by a functional assay of synthetic polymorphic OPN peptides of MRL and C3H type. Also we clearly indicated that the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-alpha, IL-lbeta and IFN-gamma in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis. On the other hand, Opn expression level in autoimmune prone mice were reported higher than that in disease resistant mice, in vitro. To determine whether qualitative (functional) difference or quantitative difference of Opn implicated in the development of autoimmune disease, we carried out the analyses as follows: 1) we generated mutant Opn peptides which were modified in substituted amino acid between two alleles followed by functional analyses of cell binding affinity 2) To determine the allelic difference of Opn expression in vivo, we made selective recombinant congenic mice of Opn gene locus which have C3H allele Opn in MRL background, 3) and then, carried out precise analyses of recombinant congenic mice.
1) Amino acid substitution by allelic polymorphism modified cell binding affinity of Opn.
2) The expression level of Opn was manifested to be controlled by Opn allele.
3) Incidence and severity of glomerulonephritis as well as livability of individuals probably via modification of cytokine properties which includes Th1/Th2 balance.
These results suggest that an amino acid substitution in allelic polymorphism of murine Opn as well as that in promoter polymorphism may play a critical role for the development of glomerulonephritis in MRL/lpr mice.

Research Products

• [Journal Article] Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. (2007)
  • Author(s): Hasegawa, H., Inoue, A., Muraoka, M., Yamanouchi, J., Miyazaki, T., Yasukawa M.
  • Journal Title: Arthritis Research and Therapy 9・1(In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. (2007)
  • Author(s): Hasegawa, H., Inoue, A., Muraoka, M., Yamanouchi, J., Miyazaki, T., Yasukawa, M.
  • Journal Title: Arthritis Res Ther 9(1)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An epistatic effect of the female-specific loci on the development of autoimmune vasculitis and anti-nuclear autoantibody in murine lupus. (2006)
  • Author(s): Zhang MC, Misu N, Miyazaki T, Nose M, Ono M. et al.
  • Journal Title: Annuals of the Rheumatic diseases 65・4 Pages: 495-500
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice. (2006)
  • Author(s): Komori, H., Furukawa, H., Mori, S., Nose, M., Ono M.et al.
  • Journal Title: Journal of Immunology 176・1 Pages: 395-400
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Augmentation of osteopontin expression in renal tubuli is independent of a histopathological type of glomerular lesions in mouse lupus nephritis. (2006)
  • Author(s): Sasaki, Y., Yamamoto, Y., Miyazaki, T., Ito, M, R., Nose, M., Watanabe, M.
  • Journal Title: Pathology International 56・3 Pages: 135-143
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antagonist of interferon-inducible protein 1O/CXCL1O ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice. (2006)
  • Author(s): Hasegawa, H., Inoue, A., Miyazaki, T., Yoshie, O., Nose, M.et a1.
  • Journal Title: Arthritis and Rheumatism 54・4 Pages: 1174-1183
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. (2006)
  • Author(s): Kohno, M., Hasegawa, H., Inoue, A., Muraoka, M., Miyazaki, T., Oka, K., Yasukawa, M.
  • Journal Title: Biochemical and biophysical research communications 347・3 Pages: 827-832
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis. (2006)
  • Author(s): Yoshida, M., Saiga, K., Furukawa, H., Terada, M., Maeyama, K., Nemoto, K., Nose, M., Ono, M.et al.
  • Journal Title: Arthritis and Rheumatism 54・9 Pages: 2934-2943
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic characterisation of spontaneous ankylosing arthropathy with unique inheritance from Fas-deficient strains of mice. (2006)
  • Author(s): Mori, S., Zhang, M, C., Tanda, N., Date, F., Nose, M., Furukawa, H., Ono, M.
  • Journal Title: Annuals of Rheumatic Diseases 65・10 Pages: 1273-1278
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice. (2006)
  • Author(s): Muraoka, M., Hasegawa, H., Kohno, M., Inoue, A., Miyazaki, T., Nose, M.et al.
  • Journal Title: Arthritis and Rheumatism 54・11 Pages: 3591-3600
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] NK026680, a novel suppressant of dendritic cell function, prevents the development of rapidly progressive glomerulonephritis and perinuclear antineutrophil cytoplasmic antibody in SCG/Kj mice. (2006)
  • Author(s): Saiga, K., Tokunaka, K., Ichimura, E., Toyoda, E., Abe, F., Yoshida, M., Furukawa, H., Nose, M., Ono, M.
  • Journal Title: Arthritis and Rheumatism 54・11 Pages: 3707-3715
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An epistatic effect of the female specific loci on the development of autoimmune vasculitis and antinuclear autoantibody in murine lupus. (2006)
  • Author(s): Zhang, M, C., Misu, N., Furukawa, H., Watanabe, Y., Terada, M., Komori, H., Miyazaki, T., Nose, M., Ono, M.
  • Journal Title: Ann Rheum Dis 65(4) Pages: 495-500
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice. (2006)
  • Author(s): Komori, H., Furukawa, H., Mori, S., Ito, M, R., Terada, M., Zhang, M, C., Ishii, N., Sakuma, N., Nose, M., Ono, M.
  • Journal Title: J Immunol 176(1) Pages: 395-400
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Polygene network in vasculitis syndrome. (2006)
  • Author(s): Nose M.
  • Journal Title: J Clinical and Experimental Medicine (Igaku no Ayumi) 214(1) Pages: 5-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of osteopontin expression in renal tubuli is independent of a histopathological type of glomerular lesions in mouse lupus nephritis. (2006)
  • Author(s): Sasaki, Y., Yamamoto, Y., Miyazaki, T., Ito, M, R., Nose, M., Watanabe, M.
  • Journal Title: Pathol Int 56(3) Pages: 135-143
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice. (2006)
  • Author(s): Hasegawa, H., Inoue, A., Kohno, M., Muraoka, M., Miyazaki, T., Terada, M., Nakayama, T., Yoshie, 0., Nose, M., Yasukawa, M.
  • Journal Title: Arthritis Rheum 54 (4) Pages: 1174-1183
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. (2006)
  • Author(s): Kohno, M., Hasegawa, H., Inoue, A., Muraoka, M., Miyazaki, T., Oka, K., Yasukawa, M.
  • Journal Title: Biochem Biophys Res Commun 347 (3) Pages: 827-832
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis. (2006)
  • Author(s): Yoshida, M., Saiga, K., Furukawa, H., Terada, M., Maeyama, K., Nemoto, K., Nose, M., Ono, M.et al.
  • Journal Title: Arthritis Rheum 54(9) Pages: 2934-2943
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic characterisation of spontaneous ankylosing arthropathy with unique inheritance from Fas-deficient strains of mice. (2006)
  • Author(s): Mori, S., Zhang, M, C., Tanda, N., Date, F., Nose, M., Furukawa, H., Ono, M.
  • Journal Title: Ann Rheum Dis 65 (10) Pages: 1273-1278
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice. (2006)
  • Author(s): Muraoka, M., Hasegawa, H., Kohno, M., Inoue, A., Miyazaki, T., Terada, M., Nose, M., Yasukawa, M.
  • Journal Title: Arthritis Rheum 54 (11) Pages: 3591-3600
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NK026680, a novel suppressant of dendritic cell function, prevents the development of rapidly progressive glomerulonephritis and perinuclear antineutrophil cytoplasmic antibody in SCG/Kj mice. (2006)
  • Author(s): Saiga, K., Tokunaka, K., Ichimura, E., Toyoda, E., Abe, F., Yoshida, M., Furukawa, H., Nose, M., Ono, M.
  • Journal Title: Arthritis Rheum 54 (11) Pages: 3707-3715
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/Ipr mice. (2005)
  • Author(s): Miyazaki T, Ono M, Sawasaki T, Endo Y, Nose M. et al.
  • Journal Title: European Journal of Immunology 35・5 Pages: 1510一1520
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice. (2005)
  • Author(s): Oishi H, Miyazaki T, Mizuki S, Nose M. et al.
  • Journal Title: Arthritis and Rheumatism 52・3 Pages: 959-966
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Characterization of histopathology and gene-expression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens. (2005)
  • Author(s): Tsubaki T, Arita N, Kawakami T, Yamamoto S, Nose M. et al.
  • Journal Title: Arthritis Research and Therapy 7・4 Pages: 825-836
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. (2005)
  • Author(s): Tsubaki T, Takegawa S, Yamamoto S, Yosie O, Nose M. et al.
  • Journal Title: Clinical and Experimental Immunology 141・2 Pages: 363-371
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antagonist of fractalkine (CX3CL1) ameliorates the initiation and progression of lupus nephritis in MRL/lpr mice. (2005)
  • Author(s): Inoue A, Hasegawa H, Kohno M, Yoshie O, Nose M, Fujita S. et al.
  • Journal Title: Arthritis and Rheumatism 52・5 Pages: 1522-1533
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 自己免疫疾患のモデル動物とゲノム解析 (2005)
  • Author(s): 小森浩章, 能勢眞人
  • Journal Title: 医学のあゆみ 213・1 Pages: 5-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] リウマチ性疾患と炎症 早期RA滑膜組織における遺伝子発現プロファイル (2005)
  • Author(s): 椿崇仁, 有田典正, 能勢眞人
  • Journal Title: Orthopaedics 18・1 Pages: 8-16
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 関節リウマチモデルのゲノム解析から学ぶもの (2005)
  • Author(s): 鴨川淳二, 水木伸一, 大石久史, 能勢眞人
  • Journal Title: ゲノム医学 5・1 Pages: 11-19
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 血管炎のポリジーンネットワーク (2005)
  • Author(s): 能勢眞人
  • Journal Title: 医学のあゆみ 214・1 Pages: 5-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice. (2005)
  • Author(s): Miyazaki, T., Ono, M., Qu, W, M., Zhang, M, C., Mori, S., Nakatsuru, S., Nakamura, Y., Sawasaki, T.Endo, Y., Nose, M.
  • Journal Title: Eur J Immunol 35 (5) Pages: 1510-1520
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice. (2005)
  • Author(s): Oishi, H., Miyazaki, T., Mizuki, S., Kamogawa, J., Lu, L, M., Tsubaki, T., Arita, N., Ono, M., Yamamoto, H., Nose, M.
  • Journal Title: Arthritis Rheum 52 Pages: 959-966
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of histopathology and gene-expression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens (2005)
  • Author(s): Tsubaki T, Arita N, Kawakami T, Yamamoto S, Nose M. et al.
  • Journal Title: Arthritis Res Ther 7 (4) Pages: 825-836
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. (2005)
  • Author(s): Tsubaki T, Takegawa S, Yamamoto S, Yosie 0, Nose M. et al.
  • Journal Title: Clin Exp Immunol 141(2) Pages: 363-371
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice. (2005)
  • Author(s): Inoue, A., Hasegawa, H., Kohno, M., Ito, M, R., Terada, M., Imai, T..Yoshie, O., Nose, M., Fujita, S.
  • Journal Title: Arthritis Rheum 52(5) Pages: 1522-1533
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Model animals of autoimmune diseases and genome analyses. (2005)
  • Author(s): Komori H, Nose M.
  • Journal Title: J Clinical and Experimental Medicine (Igaku no Ayumi) 213 (1) Pages: 5-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rheumatic diseases and inflammation; Genome expression profiles in synovial tissue of early rheumatoid arthritis. (2005)
  • Author(s): Tsubaki T., Arita M., Nose M.
  • Journal Title: Orthopaedics 18(10) Pages: 8-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lessons from genome analyses in model of rheumatoid arthritis. (2005)
  • Author(s): Kamogawa J., Mizuki S., Ohishi H., Nose M.
  • Journal Title: Genome Medicine 5(1) Pages: 11-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 病理と臨床 23巻臨時増刊 膠原病の診断マニュアル (2005)
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  • Publisher: 文光堂(東京)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Annual Review 2006 免疫 (2005)
  • Author(s): 能勢眞人, 小森浩章 他(分担執筆)
  • Total Pages: 242
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 血管炎アトラス (2005)
  • Author(s): 能勢眞人, 宮崎龍彦 他(分担執筆)
  • Total Pages: 97
  • Publisher: 厚生労働省 難治性血管炎に関する調査研究班
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Manual for pathological diagnosis of collagen diseases. (Ozaki S., Nose M.Ed) (2005)
  • Author(s): Nose, M., Miyazaki T., et al.
  • Total Pages: 303
  • Publisher: Bunko do (Tokyo)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Atlas of Vasculitis.(Ozaki S., Yoshiki K.Ed) (2005)
  • Author(s): Nose, M., Miyazaki T., et al.
  • Total Pages: 97
  • Publisher: Research Group for vasculitis syndrome (Tokyo)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Annual Review 2006, Immunology. (Okumura K., Hirano T., Sato S.Ed.)
  • Author(s): Nose, M., Komori H., et al.
  • Total Pages: 242
  • Publisher: Chugai Igaku (Tokyo)
  • Description: 「研究成果報告書概要(欧文)」より