Ossification of the Pposterior Longitudinal Ligament

• Project/Area Number: 17209012
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Tokai University (2006-2007); The University of Tokyo (2005)
• Principal Investigator: INOUE Ituro Tokai University, School of Medicine, Professor (00192500)
• Co-Investigator(Kenkyū-buntansha): TAJIMA Atsushi Tokai University, School of Medicine, Assistant Professor (10396864)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥51,610,000 (Direct Cost: ¥39,700,000、Indirect Cost: ¥11,910,000); Fiscal Year 2007: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2006: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2005: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000)
• Keywords: OPLL / ectopic ossification / expression profile / association study / SNP / Microarray analysis / アソシエーション・スタディ / 靭帯骨化

Research Abstract

To understand the molecular pathogenesis of ossification of the posterior longitudinal ligament of the spine (OPLL), an ectopic bone formation disease, we performed c_DNA microarray analysis on cultured ligament cells from the OPLL patients to understand the molecular pathogenesis of OPLL.We identified Zinc finger protein145 (PLZF) as one of up-regulated genes and tumor necrosis factor-a stimulated gene6 (TSG-6) and one of down-regulated gene during osteoblastic differentiation. We investigated the roles of PLZF in the regulation of osteoblastic differentiation of h_MSC_s and C2C12 cells.siRNA-mediated gene-silencing of PLZF resulted in a reduction of the expression of osteoblast-specific genes such as the alkaline phosphatase (ALP), collagen 1A1 (COL1A1), Runx2/cbfal (CBFA1), and osteocalcin (OCN) genes in the presence of OS in hMSCs.The overexpression of PLZF can induce CBFA1 induction suggestiong PLZF is an upstream regulator of CBFA1 and thereby might participate in promoting the ossification of spinal ligament cells in OPLL patients. Adenoirus-mediated TSG-6 overexpression in hMSCs resulted in suppression of oseoblastic differentiation induced by either BMP-2 or OS.TSG-6 can bind to BMP-2 directly, thereby could inhibit BMP-2 signaling.Taken together, these findings indicate that PLZF and TSG-6 play important roles in early osteoblastic differentiation.

Research Products

• [Journal Article] Genome-wide association analysis with selective genotyping identifies candidate loci for adult height at 8q21.13 and 15q22.33-q23 in Mongolians (2008)
  • Author(s): Kimura T, Kobayashi T, Munkhbat B, Oyungerel G, Bilegtsaikhan T, Anar D, Jambaldorj J, Munkhsaikhan S, Munkhtuvshin N, Hayashi H, Oka A, Inoue I, Inoko H.
  • Journal Title: Hum Genet
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Analysis of expressed sequence tags from liver in cynomolgus monkey(Macacafasciccularis):A systematic identification of drug-metabolizing enzyme genes (2008)
  • Author(s): Uno Y, Suzuki Y, Wakaguri H, Sakamoto Y, Sano H, Osada N, Hashimoto K, Sugano S, Inoue I.
  • Journal Title: FEBS Let
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Large-scale analysis of Macacafasciccularis transcripts and inference of genetic divergence between M.fasciccularis and M.mulatta (2008)
  • Author(s): Osada N, Hashimoto K, Kameoka Y, Hirata M, Tamura R, Uno Y, Inoue I, Hida M, Suzuki Y, Sugano S, Terao K, Kusuda J, Takahashi I.
  • Journal Title: BMC Genomics 9 Pages: 90-90
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Integration of hepatitis B virus DNA into the MPP(mixed lineage leukemia)4 gene and rearrangements of MLL4 in human hepatocellular carcinoma cells (2008)
  • Author(s): Saigo K, Yoshida K, Ikeda R, Sakamoto Y, Murakami Y, Urashima T, Asano T, Kenmochi T, Inoue I.
  • Journal Title: Hum Mutat 29 Pages: 703-708
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Further evidence for an association between mandibular height and the growth hormone receptor gene in the Japanese population (2008)
  • Author(s): Tomoyasu Y, Yamaguchi T, Tajima A, Nakajima T, Inoue I, Maki K.
  • Journal Title: Am J Ortho and Dento Ortho
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Citrin/mitochondrial glycerol 3-phosphate dehydrogenase double-knockout mice recapitulate features of human citrin deficiency (2008)
  • Author(s): Saheki T, Iijima M, Li MX, Kobayashi K, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowaki T, Sinasac DS, Tsui LC, Tsuji M, Okano A, Kobayashi T.
  • Journal Title: J Biol Chem 282 Pages: 25041-254052
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genome-wide association analysis with selective genotyping identifiescandidate loci for adult height at 8g21.13 and 15q22.33-q23 in Mongolians (2008)
  • Author(s): Kimura, T, Kobayashi, T, Munkhbat, B, Oyungerel, G, Bilegtsaikhan, T, Anar, D, Jambaldorj, J, Munkhsaikhan, S, Munkhtuvshin, N, Hayashi, H, Oka, A, Inoue, I, Inoko, H
  • Journal Title: Hum Genet (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Large-scale analysis of Macacafasciccularis transcripts and inference of genetic divergence between M.fasciccularis and M.mulatta (2008)
  • Author(s): Osada, N, Hashimoto, K, Kameoka, Y, Hirata, M, Tamura, R, Uno, Y, Inoue, I, Hida, M, Suzuki, Y, Sugano, S, Terao, K, Kusuda, J, Takahashi, I
  • Journal Title: BMC Genomics 9 Pages: 90-90
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Integration of hepatitis B virus DNA into the MPP(mixed lineage leukemia)4gene and rearrangements of MLL4 in human hepatocellular carcinoma cells (2008)
  • Author(s): Saigo, K, Yoshida, K, Ikeda, R, Sakamoto, Y, Murakami, Y, Urashima, T, Asano, T, Kenmochi, T, Inoue, I
  • Journal Title: Hum Mutati 29 Pages: 703-708
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Further evidence for an association between mandibular height and the growth hormone receptor gene in the Japanese population (2008)
  • Author(s): Tomoyasu Y, Yamaguchi T, Tajima A, Nakajima T, Inoue I, Maki K.
  • Journal Title: Am J Ortho and Dento Ortho (in press)
  • Peer Reviewed
• [Journal Article] Gene expression changes during the chondrogenic differentiation of human mesenchymal stem cells (2008)
  • Author(s): Ikeda R, Tukahara S, Yoshida K, Inoue I.
  • Journal Title: J Biol sci (in press)
  • Peer Reviewed
• [Journal Article] Gene expression changes during the chondrogenic differentiation of human mesenchymal stem cells (2007)
  • Author(s): Ikeda R, Tsukahara S, Yoshida K, Inoue I.
  • Journal Title: J Biol Sci 7 Pages: 729-736
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification of FAZF as a novel BMP2-induced transcription factor during osteoblastic differentiation (2007)
  • Author(s): Ikeda R, Yoshida K, Inoue I.
  • Journal Title: J Cell Biochem 101 Pages: 147-154
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Citrin/mitochondrial glycerol 3-phosphate dehydrogenase double-knockout mice recapitulate features of human citrin deficiency (2007)
  • Author(s): Saheki, T, Iijima, M, Li, MX, Kobayashi, K, Horiuchi, M, Ushikai, M, Okumura, F, Meng, XJ, Inoue, I, Tajima, A, Moriyama, M, Eto, K, Kadowaki, T, Sinasac, DS, Tsui, LC, Tsuji, M, Okano, A, Kobayashi, T
  • Journal Title: J BiolChem 282 Pages: 25041-25052
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gene expression changes during the chondrogenic differentiation of human mesenchymal stem cells (2007)
  • Author(s): Ikeda, R, Tsukahara, S, Yoshida, K, Inoue, I
  • Journal Title: J BiolSci 7 Pages: 729-736
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of FAZF as a novel BMP2-induced transcription factor during osteoblastic differentiation (2007)
  • Author(s): Ikeda, R, Yoshida, K, Inoue, I
  • Journal Title: J Cell Biochem 101 Pages: 147-154
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Citrin/mitochondrial glycerol 3-phosphate dehydrogenase double-knockout micerecapitulate features of human citrin deficiency (2007)
  • Author(s): Saheki T, Iijima M, Li MX, Kobayashi k, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowakir T, Sinasac DS, Tsui LC, Tsuji M, Okano A, Kobayashi T.
  • Journal Title: J Biol Chem 282 Pages: 25041-254052
  • Peer Reviewed
• [Journal Article] Increased expression of ephrin A1 in brain arteriovenous malformation. (2007)
  • Author(s): Sasahara A, Kasuya H, Akagawa H, Ujue H, Kubo O, Sasaki T, Onda H, sakamoto Y, Krischek B, Hori T, Inoue I.
  • Journal Title: Neurosurg Rev 30 Pages: 299-305
  • Peer Reviewed
• [Journal Article] Identification of FAZF as a novel BMP2-induced transcription factor during osteoblastic defferentiatin. (2007)
  • Author(s): Ikeda R, Yoshida K, Inoue I.
  • Journal Title: J Cell Biochem 101 Pages: 147-154
  • Peer Reviewed
• [Journal Article] Identification of FAZF as a novel BMP2-induced transcription factor during osteoblastic differentiation (2007)
  • Author(s): Ikeda R, Yoshida K, Inoue I
  • Journal Title: J Cell Biochem in press
• [Journal Article] Pathopysiological role of endothelin in ectopic ossification of human spinal ligaments induced by mechanical stress (2006)
  • Author(s): Iwasawa T, Iwasaki K, Sawada T, Okada A, Ueyama K, Motomura S, Harata S, Inoue I, Toh S, Furukawa K-I.
  • Journal Title: Calcif Tissue Int 79 Pages: 422-430
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation (2006)
  • Author(s): Ikeda R, Yoshida K, Ushiyama M, Yamaguchi T, Iwashita K, Futagawa T, Shibayama Y, Oiso S, Takeda Y, Kariyazono H, Furukawa T, Nakamura K, Akiyama S, Inoue I, Yamada K.
  • Journal Title: BiolPharm Bull 29 Pages: 815-819
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor alpha stimulated gene-6 inhibits osteoblastic differentiation of human mesenchymal stem cells induced by OS and BMP-2 (2006)
  • Author(s): Tsukahara S, Ikeda R, Goto S, Yoshida K, Mitsumori R, Sakamoto Y, Tajima A, Yokoyama T, Toh S, Furukawa K, Inoue I.
  • Journal Title: Biochem J 398 Pages: 595-603
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [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 Pages: 611-616
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients (2006)
  • Author(s): Krischek B, Kasuya H, Akagawa H, Tajima A, Narita A, Onda H, Hori T, Inoue I
  • Journal Title: J Neurosurg 105 Pages: 717-722
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Zebrafish numb homologue:phylogenetic evolution and involvement in regulation of left-right asymmetry (2006)
  • Author(s): Niikura Y, Tabata Y, Tajima A, Inoue I, Arai K, Watanabe S.
  • Journal Title: Mech Dev 123 Pages: 407-414
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genetic susceptibility to OPLL (2006)
  • Author(s): Inoue I.In: Yonenobu K, Nakamura K, Toyama Y
  • Journal Title: Ossification of the posterior longitudinal ligament. Pages: 19-25
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pathopysiological role of endothelin in ectopic ossification of human spinal ligaments induced by mechanical stress (2006)
  • Author(s): Iwasawa, T, Iwasaki, K, Sawada, T, Okada, A, Ueyama, K, Motomura, S, Harata, S, Inoue, I, Toh, S, Furukawa, K-I
  • Journal Title: Calcif Tissue Int 79 Pages: 422-430
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation (2006)
  • Author(s): Ikeda, R, Yoshida, K, Ushiyama, M, Yamaguchi, T, Iwashita, K Futagawa, T, Shibayama, Y, Oiso, S, Takeda, Y, Kariyazono, H, Furukawa, T, Nakamura, K, Akiyama, S, Inoue, I, Yamada, K
  • Journal Title: BiolPharm Bull 29 Pages: 815-819
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tumor necrosis factor alpha stimulated gene-6 inhibits osteoblastic differentiation of human mesenchymal stem cells induced by OS and BMP-2 (2006)
  • Author(s): Tsukahara, S, Ikeda, R, Goto, S, Yoshida, K, Mitsumori, R, Sakamoto, Y, Tajima, A, Yokoyama, T, Toh, S, Furukawa, K, Inoue, I
  • Journal Title: Biochem 398 Pages: 595-603
  • 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 Pages: 611-616
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients (2006)
  • Author(s): Krischek, B, Kasuya, H, Akagawa, H, Tajima, A, Narita, A, Onda, H, Hori, T, Inoue, I
  • Journal Title: J Neurosurg 105 Pages: 717-722
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Zebrafish numb homologue : phylogenetic evolution and involvement in regulation of (2006)
  • Author(s): Niikura, Y, Tabata, Y, Tajima, A, Inoue, I, Arai, K, Watanabe, S
  • Journal Title: left-right asymmetry 123 Pages: 407-414
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] K-I Psthopysiological roles of endothelin in ectopic ossification of human spinal ligaments induced by mechanical stress (2006)
  • Author(s): Iwasawa T, Iwasaki K, Sawada T, Okada A, Ueyama K, Motomura S, Harata S, Inoue I, Toh S, Furukawa
  • Journal Title: Calcif Tissue Int 79 Pages: 422-430
• [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 Pages: 611-616
• [Journal Article] The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation. (2006)
  • Author(s): Ikeda R, Yoshida K, Ushiyama M, Yamaguchi T, Iwashita K, Futagawa T, Shibayama Y, Oiso S, Takeda Y, Kariyazono H, Furukawa T, Nakamura K, Akiyama S, Inoue I, Yamada K, Krischnek B
  • Journal Title: Biol Pharm Bull 29 Pages: 815-819
• [Journal Article] Tumor necrosis factor alpha stimulated gone-6 inhibits osteoblastic differentiation of human mesenchymal stem cells induced by OS and BMP-2. (2006)
  • Author(s): Tsukahara S, Ikeda R, Goto S, Yoshida K, Mitsumori R, Sakamoto Y, Tajima A, Yokoyama T, Toh S, Furukawa K, Inoue I
  • Journal Title: Biochem J 398 Pages: 595-603
• [Journal Article] PLZF and TSG-6 identified by gene expression analysis play roles in the pathogenesis of OPLL. (2006)
  • Author(s): Inoue I, Ikeda R, Tsukahara S
  • Journal Title: J Pharmacol Sci 100 Pages: 205-210
• [Journal Article] The promyelotic leukemia zinc finger promotes osteoblastic differentiation of human mesenchymal stem cells as an upstream regulator of CBFA1 (2005)
  • Author(s): Ikeda R, Yoshida K, Tsukahara S, Sakamoto Y, Tanaka H, Furukawa-K, Inoue I.
  • Journal Title: J Biol Chem 280 Pages: 8523-8530
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] COL6A1,the candidate gene for ossification of posterior longitudinal ligament,is associated with diffuse idiopathic skeletal hyperostosis in Japanese (2005)
  • Author(s): Tsukahara S, Miyazawa N, Akagawa H, Forejtova S, Pavelka K, Tanaka T, Toh S, Tajima A, Akiyama I, Inoue I.
  • Journal Title: Spine 30 Pages: 2321-2324
  • NAID: 10020578412
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genome-wide linkage analysis of mandibularprognathism in Korean and Japanese patients (2005)
  • Author(s): Yamaguchi T, Park S-B, Narita A, Maki K, Inoue I.
  • Journal Title: J Dent Res 84 Pages: 255-259
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Evidence for natural selection in the HAVCR1 gene : high degree of amino-acid variability in the mucin domain of human HAVCR1 protein. (2005)
  • Author(s): Nakajima T, Wooding S, Satta Y, Jinnai N, Goto S, Hayasaka I, Saitou N, Guan-Jun J, Tokunaga K, Jorde LB, Emi M, Inoue I.
  • Journal Title: Genes Immun 6 Pages: 398-406
• [Journal Article] PLZF promotes osteoblastic differentiation of human mesenchymal stem cells as an upstream regulator of CBFA1. (2005)
  • Author(s): Ikeda R, Yoshida K, Tsukahara S, Sakamoto Y, Tanaka H, Furukawa-K, Inoue I.
  • Journal Title: J Biol Chem 280 Pages: 8523-8530
• [Journal Article] COL6A1, the candidate gene for ossification of posterior longitudinal ligament, is associated with diffuse idiopathic skeletal hyperostosis in Japanese. (2005)
  • Author(s): Tsukahara S, Miyazawa N, Akagawa H, Forejtova S, Pavelka K, Tanaka T, Toh S, Tajima A, Akiyama I, Inoue I.
  • Journal Title: Spine 30 Pages: 2321-2324
  • NAID: 10020578412
• [Journal Article] Genome-wide linkage analysis of mandibular prognathism in Korean and Japanese patients. (2005)
  • Author(s): Yamaguchi T, Park S-B, Narita A, Maki K, Inoue I.
  • Journal Title: J Dent Res 84 Pages: 255-259
• [Journal Article] Analysis of expressed sequence tags from liver in cynomolgus monkey(Macacafasciccularis) : A systematic identification of drug-metabolizing enzyme genes
  • Author(s): Uno, Y, Suzuki, Y, Wakaguri, H, Sakamoto, Y, Sano, H, Osada, N, Hashimoto, K, Sugano, S, Inoue, I
  • Journal Title: FEBS Lat (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Further evidence for an association between mandibular height and the growth hormone receptor gene in the Japanese population
  • Author(s): Tomoyasu, Y, Yamaguchi, T, Tajima, A, Nakajima, T, Inoue, I, Maid, K
  • Journal Title: Am J Ortho and Dente Ortho (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PLZF and TSG-6 identified by gene expression analysis play roles in the pathogenesis of OPLL.
  • Author(s): Inoue I, Tsukahara S.
  • Journal Title: J Pharmacol Sci (in press)
• [Journal Article] Zebrafish numb homologue : phylogenetic evolution and involvement in regulation of left-right asymmetry.
  • Author(s): Niikura Y, Tabata Y, Tajima A, Inoue I, Arai K, Watanabe S.
  • Journal Title: Mech Dev (in press)
• [Book] Ossification of the posterior longitudinal ligament. (2006)
  • Author(s): Inoue I, Yonenobu K, Nakamura K, Toyama Y(eds)
  • Total Pages: 305
  • Publisher: Springer,Tokyo
• [Book] Ossification of the posterior longitudinal ligament.
  • Author(s): Inoue I.(Yonenobu K, Nakamura K, Toyama Y(eds))
  • Publisher: Springer, Tokyo(in press)