Molecular pathogenesis of lumbar disc degeneration

• Project/Area Number: 17209050
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: RIKEN
• Principal Investigator: IKEGAWA Shiro RIKEN, Laboratory for Bone and Joint diseases, Team leader, 変形性関節症関連遺伝子研究チーム, チームリーダー (30272496)
• Co-Investigator(Kenkyū-buntansha): INABA Ikuyo RIKEN, Laboratory for Bone and Joint diseases, Research associate, 変形性関節症関連遺伝子研究チーム, リサーチアソシエイト (60415081)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥41,080,000 (Direct Cost: ¥31,600,000、Indirect Cost: ¥9,480,000); Fiscal Year 2006: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2005: ¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000)
• Keywords: Lumbar disc disease / herniation / susceptibility gene / association study / CILP / 椎間板ヘルニア / 分子病態 / ゲノム / SNP / 遺伝子多型

Research Abstract

We aimed to identify the susceptibility genes for lumbar disc disease (LDD)/lumbar disc herniation (LDH) and to clarify their molecular mechanism. Through the analysis of the genes and their disease-causing sequence variations, we obtained the following results:
1) By a case-control association study, we identified CILP (cartilage intermediate layer protein) as a susceptibility gene for LDD (Seki et al. Nature Genet, 2005). This is the first LDD gene harboring convincing functional proof. Furthermore, we discovered that CILP binds to TGF-β, and inhibit its effect on growth and differentiation of intervertebral disc cartilage.
2) We have clarified the mechanism of transcriptional regulation of CILP (Mori et al. Biochem Biophys Res Commun,2006).
3) We examined association of COL9A2 and COL9A3that encode a2(IX), a3(IX) chains of type IX collagen, and found that Japanese may have a different susceptibility gene from European (Seki et al. J Hum Genet, 2006). Also, we found no association in the previously reported genes, MMP3, VDR and AGC1 in Japanese LDD.
4) We discovered the association of LDH with type XI collagen gene (manuscript in submission).

Research Products

• [Journal Article] Transcriptional regulation of the cartilage intermediate layer protein (CILP) gene. (2006)
  • Author(s): Mori M, Nakajima M, Mikami Y, Seki S, Takigawa M, Kubo T, Ikegawa S
  • Journal Title: Biochem Biophys Res Commun 341 (1) Pages: 121-127
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association study of COL9A2 with lumbar disc disease in the Japanese population. (2006)
  • Author(s): Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S
  • Journal Title: J Hum Genet 51 (12) Pages: 1063-1067
  • NAID: 10018641536
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. (2006)
  • Author(s): Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, Hirabayashi S, Sugimori K, Matsumoto M, Kawaguchi H, Takahashi M, Inoue H, Kimura T, Matsusue Y, Inoue I, Baba H, Nakamura K, Ikegawa S
  • Journal Title: Hum Genet 119 (6) Pages: 611-616
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transcriptional regulation of the cartilage intermediate layer protein (CILP) gene. (2006)
  • Author(s): Mori M, Nakajima M, Mikami Y, Seki S, Takigawa M, Kubo T, Ikegawa S.
  • Journal Title: Biochem Biophys Res Commun 341.1 Pages: 121-127
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association study of COL9A2 with lumbar disc disease in the Japanese population. (2006)
  • Author(s): Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S.
  • Journal Title: J Hum Genet 51.12 Pages: 1063-1067
  • NAID: 10018641536
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. (2006)
  • Author(s): Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, Hirabayashi S, Sugimori K, Matsumoto M, Kawaguchi H, Takahashi M, Inoue H, Kimura T, Matsusue Y, Inoue I, Baba H, Nakamura K, Ikegawa S.
  • Journal Title: Hum Genet 119.6 Pages: 611-616
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. (2006)
  • Author(s): Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, Hirabayashi S, Sugimori K, Matsumoto M, Inoue H, Kimura T, Matsusue Y, Inoue I, Baba H, Nakamura K, Ikegawa S.
  • Journal Title: Hum Genet 119・6 Pages: 611-616
• [Journal Article] Transcriptional regulation of the cartilage intermediate layer protein (CILP) gene. (2006)
  • Author(s): Mori M, Nakajima M, Mikami Y, Seki S, Takigawa M, Kubo T, Ikegawa s.
  • Journal Title: Biochemical and Biophysical Research Communications 341・1 Pages: 121-127
• [Journal Article] Association study of COL9A2 with lumbar disc disease in the Japanese population. (2006)
  • Author(s): Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S.
  • Journal Title: Journal of Human Genetics 51・12 Pages: 1063-1067
  • NAID: 10018641536
• [Journal Article] Transcriptional regulation of the cartilage intermediate layer protein (CILP) gene. (2006)
  • Author(s): Masaki Mori
  • Journal Title: Biochemical and biophysical research communications (Epub ahead of print)
• [Journal Article] A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. (2005)
  • Author(s): Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio E, Mori M, Miyamoto Y, Masuda I, Tsunoda T, Kamata M, Kubo T, Toyama Y, Kimura T, Nakamura Y, Ikegawa S
  • Journal Title: Nature Genet 37 (6) Pages: 607-612
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MATN and LAPTM are parts of larger transcription units produced by intergenic splicing : intergenic splicing may be a common phenomenon. (2005)
  • Author(s): Maeda K, Horikoshi T, Nakashima E, Miyamoto Y, Mabuchi A, Ikegawa S
  • Journal Title: DNA Res 12 (5) Pages: 365-372
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease (2005)
  • Author(s): Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, Tsunoda T, Kamata M, Kubo T, Toyama Y, Kimura T, Nakamura Y, Ikegawa S.
  • Journal Title: Nature Genet 37.6 Pages: 607-612
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MATN and LAPTM are parts of larger transcription units produced by intergenic splicing : intergenic splicing may be a common phenomenon. (2005)
  • Author(s): Maeda K, Horikoshi T, Nakashima E, Miyamoto Y, Mabuchi A, Ikegawa S.
  • Journal Title: DNA Res 12.5 Pages: 365-37
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional SNP in CILP, encoding cartilage intermediate layer protein is associated with susceptibility to lumbar disc disease. (2005)
  • Author(s): Shoji Seki
  • Journal Title: Nature Genetics 37・6 Pages: 607-612
• [Journal Article] 椎間板ヘルニアの原因遺伝子CILP (2005)
  • Author(s): 池川 志郎
  • Journal Title: 医学のあゆみ 214・9 Pages: 755-756
• [Patent(Industrial Property Rights)] 椎間板変性症関連疾患感受性遺伝子およびその用途 (2005)
  • Inventor(s): 池川志郎
  • Industrial Property Rights Holder: 独立行政法人理化学研究所
  • Industrial Property Number: 2005-292359
  • Filing Date: 2005-10-05
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 椎間板変性関連疾患感受性遺伝子およびその用途 (2005)
  • Inventor(s): 池川 志郎
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 2005-292359
  • Filing Date: 2005-10-05