The role of periostin for the pathogenesis of ossification of the posterior longitudinal ligament

• Project/Area Number: 19K09545
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: University of Toyama
• Principal Investigator: Kawaguchi Yoshiharu 富山大学, 学術研究部医学系, 教授 (00262527)
• Co-Investigator(Kenkyū-buntansha): 北島 勲 富山大学, 大学本部, 理事・副学長 (50214797) ; 箭原 康人 富山大学, 附属病院, 医員 (60456390)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脊柱靭帯骨化症 / 後縦靭帯骨化症 / 骨化巣伸展 / ペリオスチン / リン代謝 / 血清リン値 / FGF-23 / バイオマーカー / 血清バイオマーカー / 血清ペリオスチン / 骨化進展 / OS index / Sclerostin(SOST) / Dickkopf-1(DKK1) / 脊椎脊髄病学 / 骨化関連因子

Outline of Research at the Start

微小炎症とペリオスチンの上昇が、脊柱靭帯骨化症の発症に関与していることがわかった。しかしその機序は不明である。この問題を解決するため、①脊柱靭帯骨化症患者検体を用いた、血清ペリオスチンおよび骨化関連因子の検証、②骨化最前線における前駆細胞(Ossification initiating cell: OIC)の分離・培養、③OICに対するIL-23/IL-17/ペリオスチン経路の意義と作用を検証、④脊柱靭帯骨化症モデルマウスに対する、ペリオスチン欠損、IL-17阻害の意義を検証、以上を解明し脊柱靱帯骨化症の治療法の開発を目指すことを目的とする。

Outline of Final Research Achievements

The etiology of ossification of the posterior longitudinal ligament (OPLL) has not been fully elucidated yet. This study included 92 patients with OPLL and 54 control patients. The case–control analysis was performed. The serum fibroblast growth factor-23 (FGF-23), creatinine (Cre), inorganic phosphate (Pi), calcium (Ca), alkaline phosphatase, and periostin levels were assessed. The data were compared between patients with OPLL progression and without OPLL progression. The mean serum FGF-23 level in the OPLL group was higher than that in the control group. The serum Pi level in the OPLL group was lower than that in the control group. The mean serum periostin level in the OPLL group was higher than that in the control group. The serum periostin level in the progression group was higher than that in the nonprogression group. Based on these results, we concluded that periostin and FGF-23 are positive biomarkers for OPLL. Serum periostin level is related to OPLL progression.

Academic Significance and Societal Importance of the Research Achievements

原因不明の難病である脊柱後縦靭帯骨化症（OPLL）の病態にリン代謝とペリオスチンが関連していることが示唆された。またペリオスチンはOPLLの骨化巣の伸展に関連していることが分かった。この結果から、ペリオスチンは骨化巣の伸展の危険因子を予測するバイオマーカーになりうる可能性があると考えられた。またFGF-23を介したリン代謝を制御することによってOPLLの骨化巣を抑制する可能性があり、IL-17などの薬物療法に期待が持てる。さらにペリオスチンの制御については今後の課題であると考えられた。

Research Products

• [Journal Article] Serum Periostin Level Reflects Progression of Ossification of the Posterior Longitudinal Ligament (2022)
  • Author(s): Kawaguchi, Yoshiharu MD, PhD1,a; Kitajima, Isao MD, PhD2; Yasuda, Taketoshi MD, PhD1; Seki, Shoji MD, PhD1; Suzuki, Kayo MD, PhD1; Makino, Hiroto MD1; Ujihara, Yasuhiro MT2; Ueno, Tomohiro MT, PhD2; Canh Tung, Nguyen Tran MD1; Yahara, Yasuhito MD, PhD1
  • Journal Title: J Bone Joint Surg, open access Volume: 7 Issue: 1 Pages: 1-8
  • DOI: 10.2106/jbjs.oa.21.00111
  • Peer Reviewed / Open Access
• [Journal Article] Biomarker research approach to the pathogenesis of ossification of the spinal ligament: A review (2022)
  • Author(s): Kawaguchi Y
  • Journal Title: Spine Surgery Related Reseach Volume: 未
  • Peer Reviewed
• [Journal Article] Association Between Vitamin A Intake and Disease Severity in Early-Onset Heterotopic Ossification of the Posterior Longitudinal Ligament of the Spine (2021)
  • Author(s): Endo Tsutomu、Imagama Shiro、Kato Satoshi、Kaito Takashi、Sakai Hiroaki、Ikegawa Shiro、Kawaguchi Yoshiharu、Kanayama Masahiro、Hisada Yuichiro、Koike Yoshinao、Ando Kei、Kobayashi Kazuyoshi、Oda Itaru、Okada Kazufumi、Takagi Ryo、Iwasaki Norimasa、Takahata Masahiko
  • Journal Title: Global Spine Journal Volume: Online ahead of print Issue: 8 Pages: 1-11
  • DOI: 10.1177/2192568221989300
  • Peer Reviewed / Open Access
• [Journal Article] Severity of Myelopathy is Closely Associated With Advanced Age and Signal Intensity Change in Cervical Ossification of the Posterior Longitudinal Ligament (2021)
  • Author(s): Hirai T., Yoshii T., Egawa S., Sakai K., Kusano K., Nakagawa Y., … Okawa A
  • Journal Title: Clinical Spine Surgery: A Spine Publication Volume: Publish Ahead of Print Issue: 1 Pages: 1-11
  • DOI: 10.1097/bsd.0000000000001164
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Ossification Spread on Cervical Spine Function in Patients With Ossification of The Posterior Longitudinal Ligament (2021)
  • Author(s): Katsumi K,Hirai T,Yoshii T,Maki S,Mori K,Nagoshi N,Nishimura S,Takeuchi K,Ushio S,Furuya T,Watanabe K,Nishida N,Watanabe K,Kaito T,Kato S,Nagashima K,Koda M,Ito K,Imagama S,Matsuoka Y,Wada K,Kimura A,Ohba T,Katoh H,Matsuyama Y,Ozawa H,Haro H,Takeshita K,Watanabe M,Matsumoto M,Nakamura M,Yamazaki M,Okawa A,Kawaguchi Y
  • Journal Title: Scientific Report Pages: 1-16
  • DOI: 10.21203/rs.3.rs-216266/v1
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of ossification of the spinal ligament, 2019 (2021)
  • Author(s): Kawaguchi Yoshiharu、Imagama Shiro、Iwasaki Motoki、Kaito Takashi、Koda Masao、Chikuda Hirotaka、Hasegawa Tomohiko、Mori Kanji、Yoshii Toshitaka
  • Journal Title: Journal of Orthopaedic Science Volume: 26 Issue: 1 Pages: 1-45
  • DOI: 10.1016/j.jos.2020.07.027
  • Peer Reviewed
• [Journal Article] Clinical characteristics in patients with ossification of the posterior longitudinal ligament: A prospective multi-institutional cross-sectional study (2020)
  • Author(s): Hirai T., Yoshii T., Ushio S., Mori K., Maki S., Katsumi K.,…Kawaguchi Y.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-020-62278-3
  • Peer Reviewed / Open Access
• [Journal Article] Associations between Clinical Symptoms and Degree of Ossification in Patients with Cervical Ossification of the Posterior Longitudinal Ligament: A Prospective Multi-Institutional Cross-Sectional Study (2020)
  • Author(s): Hirai T., Yoshii T., Ushio S., Hashimoto J., Mori K, Maki S.,… Kawaguchi Y.
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 12 Pages: 4055-4055
  • DOI: 10.3390/jcm9124055
  • Peer Reviewed / Open Access
• [Journal Article] A systematic review and meta-analysis comparing anterior decompression with fusion and posterior laminoplasty for cervical ossification of the posterior longitudinal ligament (2020)
  • Author(s): Yoshii Toshitaka、Egawa Satoru、Hirai Takashi、Kaito Takashi、Mori Kanji、Koda Masao、Chikuda Hirotaka、Hasegawa Tomohiko、Imagama Shiro、Yoshida Masahiro、Iwasaki Motoki、Okawa Atsushi、Kawaguchi Yoshiharu
  • Journal Title: Journal of Orthopaedic Science Volume: 25 Issue: 1 Pages: 58-65
  • DOI: 10.1016/j.jos.2019.03.004
  • Peer Reviewed
• [Journal Article] The characteristics of the patients with radiologically severe cervical ossification of the posterior longitudinal ligament of the spine: A CT-based multicenter cross-sectional study. (2019)
  • Author(s): Kanji Mori,Toshitaka Yoshii, Yoshiharu Kawaguchi et al
  • Journal Title: J Orthop Sci Volume: 19 Issue: 5 Pages: 30313-6
  • DOI: 10.1016/j.jos.2019.09.018
  • Peer Reviewed
• [Journal Article] Biomarkers of ossification of the spinal ligament (OSL) (2018)
  • Author(s): Kawaguchi Y
  • Journal Title: Global Spine Journal Volume: - Issue: 6 Pages: 650-657
  • DOI: 10.1177/2192568218791799
  • Peer Reviewed / Open Access
• [Presentation] Recent findings for the pathophysiology and background factors of OPLL (2022)
  • Author(s): Y. Kawaguchi
  • Organizer: Cervical Spine Research Society, Asian region
  • Int'l Joint Research / Invited
• [Presentation] Ossification of the posterior longitudinal ligament (OPLL) -pathology and treatment- (2021)
  • Author(s): Y. Kawaguchi
  • Organizer: Turkey neurosurgical meeting, Izumir
  • Int'l Joint Research / Invited
• [Presentation] Management of Re-growing OPLL (2021)
  • Author(s): Y. Kawaguchi
  • Organizer: In League, AOSpine AP
  • Int'l Joint Research / Invited
• [Presentation] Enhancing postoperative functional and surgical outcomes in elderly population (2021)
  • Author(s): Y. Kawaguchi
  • Organizer: Assicon meeting
  • Int'l Joint Research / Invited
• [Presentation] More than 20 years follow-upafter cervical laminoplasty (2021)
  • Author(s): Y. Kawaguchi
  • Organizer: Spine across the sea
  • Int'l Joint Research
• [Presentation] 脊柱靭帯骨化症，明らかにしてきた知見と今後のアプローチ (2020)
  • Author(s): 川口善治
  • Organizer: 第20回山梨大学整形外科セミナー
• [Presentation] 脊柱靭帯骨化症，明らかにしてきた知見と今後のアプローチ (2020)
  • Author(s): 川口善治
  • Organizer: 第41回福岡運動器カンファレンス
• [Presentation] Sagittal balance in cervical spine- How necessary is it? (2019)
  • Author(s): Kawaguchi Y
  • Organizer: 32nd Annual Conference ASSICON 2019- Association of spine surgeons of India
• [Presentation] Is OPLL progression inevitable despite surgery? (2019)
  • Author(s): Kawaguchi Y
  • Organizer: 32nd Annual Conference ASSICON 2019- Association of spine surgeons of India
• [Presentation] Controversies in cervical spine-3 case (2019)
  • Author(s): Kawaguchi Y
  • Organizer: 32nd Annual Conference ASSICON 2019- Association of spine surgeons of India
• [Presentation] Tips & tricks in management of ossified ligamentum flavum (2019)
  • Author(s): Kawaguchi Y
  • Organizer: 32nd Annual Conference ASSICON 2019- Association of spine surgeons of India
• [Presentation] Prevalence of ossified spinal lesions in patients with ossification of the posterior longitudinal ligament (OPLL) and sex differences in distribution of OPLL- A multicenter Study (2019)
  • Author(s): Hirai T, Kawaguchi Y, Yoshii T, Nagoshi N, Takeuchi K, Mori K, Okawa A
  • Organizer: Orthopaedic Research Society 2019 annual meeting
• [Presentation] The effect of multiple lesions in patients with cervical ossification of the posterior longitudinal ligament (2019)
  • Author(s): Kawaguchi Y, Yasuda T, Seki S, Suzuki K, Makino H, Kamei K, Kimura T
  • Organizer: 10th Anniversary Meeting Cervical Spine Research Society- Asia Pacific Section (CSRS-Ap 2019)
• [Presentation] The effect of tandem resions in patients with cervical ossification of the posterior longitudinal ligament (2019)
  • Author(s): Kawaguchi Y
  • Organizer: Aospine Global Spine Congress 2019
• [Presentation] Clinical impact of ossification of the posterior longitudinal ligament progression after cervical laminoplasty (2019)
  • Author(s): Kawaguchi Y
  • Organizer: The 12th MISS (Minimally Invasive spine surgery) summit forum’19
• [Presentation] Development of a new technique for cervical pedicle screw and Magerl screw insertion using a 3-dimensional image guide (2019)
  • Author(s): Kawaguchi Y
  • Organizer: Association of Spine Surgeons of Nepal
• [Presentation] More than 20 years of follow-up after en bloc cervical laminoplasty (2019)
  • Author(s): Kawaguchi Y
  • Organizer: Association of Spine Surgeons of Nepal
• [Book] Okawa A, Matsumoto M, Iwasaki M, Kawaguchi Y. (2020)
  • Author(s): OPLL Ossification of the posterior longitudinal ligament.
  • Total Pages: 278
  • Publisher: Springer
  • ISBN: 9789811538551