Development of novel therapeutic intervention for controlling inflammatory osteolysis leading to total hip arthroplasty

• Project/Area Number: 17K10993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Hokkaido University
• Principal Investigator: Terkawi Alaa 北海道大学, 医学研究院, 助教 (00723074)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 人工股関節置換術後の無菌性緩み / マクロファージ / サイトカイン / ケモカイン / 人工関節置換術後の無菌性緩み / 炎症性骨溶解 / 破骨細胞 / IL-27 / Osteolysis / Inflammation / Osteoclastogenesis / Bone resorption / 骨融解 / 炎症反応 / インプラント

Outline of Final Research Achievements

The objective of current study is to investigate role of macrophages, DCs and neutrophils in pathogenesis of inflammatory osteolysis as a step to develop therapy for aseptic loosening. Transcriptional profiling of macrophages exposed to polyethylene UHMWPE uncovered large number of inflammatory genes that were not identified before in macrophages response to implant wear particles. Bioinformatic analysis identified IL-27 as regulatory factor in inflammatory osteolysis in addition to 2 novel osteoclastogenic factors that promote inflammation and bone resorption in vitro and in vivo. The current data provide novel and fundamental knowledge on cellular and molecular pathogenesis of osteolysis leading to aseptic loosening. Such findings shed the light on new molecular candidates for therapeutic intervention and diagnostic application. Continuing research on our identified molecules as therapeutic targeting may aid in the design of novel medications for prevention of implant loosening.

Academic Significance and Societal Importance of the Research Achievements

人工股関節置換術は股関節が高度に破壊された症例に対して行われる手術である。一般的に人工股関節の術後耐用年数は10年～20年とされるが、人工関節の「緩み」は、長期使用により関節面から発生する摩耗粉がマクロファージなどの免疫細胞を活性化し、最終的に局所的な骨溶解が引き起こされることで起こる。現在の所、「緩み」に対する治療方法は再手術しかないのが現状である。
そこで本研究では、摩耗粉と反応するマクロファージと、それに関連する因子を調べ、そのメカニズムを解析した。本研究成果から、再手術に頼らない、人工股関節の「緩み」に対する治療方法を将来的に確立することが出来ると考えている。

Research Products

• [Journal Article] Identification of IL-27 as potent regulator of inflammatory osteolysis associated with vitamin E-blended ultra-high molecular weight polyethylene debris of orthopedic implants (2019)
  • Author(s): Terkawi Mohamad Alaa、Kadoya Ken、Takahashi Daisuke、Tian Yuan、Hamasaki Masanari、Matsumae Gen、Alhasan Hend、Elmorsy Sameh、Uetsuki Keita、Onodera Tomohiro、Takahata Masahiko、Iwasaki Norimasa
  • Journal Title: Acta Biomaterialia Volume: 89 Pages: 242-251
  • DOI: 10.1016/j.actbio.2019.03.028
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Novel Cartilage Fragments Stimulation Model Revealed that Macrophage Inflammatory Response Causes an Upregulation of Catabolic Factors of Chondrocytes In Vitro (2019)
  • Author(s): Hamasaki Masanari、Terkawi Mohamad Alaa、Onodera Tomohiro、Homan Kentaro、Iwasaki Norimasa
  • Journal Title: CARTILAGE Volume: In press Issue: 3 Pages: 354-361
  • DOI: 10.1177/1947603519828426
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of Ultra-Purified Alginate Gel Implantation on Meniscal Defects in Rabbits (2018)
  • Author(s): Kim WooYoung、Onodera Tomohiro、Kondo Eiji、Kawaguchi Yasuyuki、Terkawi Mohamad Alaa、Baba Rikiya、Hontani Kazutoshi、Joutoku Zenta、Matsubara Shinji、Homan Kentaro、Hishimura Ryosuke、Iwasaki Norimasa
  • Journal Title: The American Journal of Sports Medicine Volume: 47 Issue: 3 Pages: 640-650
  • DOI: 10.1177/0363546518816690
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A mathematical model for predicting postoperative leg shortening after curved intertrochanteric varus osteotomy for osteonecrosis of the femoral head (2018)
  • Author(s): Asano Tsuyoshi、Takahashi Daisuke、Shimizu Tomohiro、Irie Tohru、Arai Ryuta、Terkawi Mohamad Alaa、Iwasaki Norimasa
  • Journal Title: PLOS ONE Volume: 13 Issue: 12 Pages: e0208818-e0208818
  • DOI: 10.1371/journal.pone.0208818
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differential Gene Expression Profile of Human Neutrophils Cultured with Plasmodium falciparum-Parasitized Erythrocytes (2018)
  • Author(s): Terkawi Mohamad Alaa、Takano Ryo、Kato Kentaro
  • Journal Title: Journal of Immunology Research Volume: 2018 Pages: 1-8
  • DOI: 10.1155/2018/6709424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Is There an Association Between Borderline-to-mild Dysplasia and Hip Osteoarthritis? Analysis of CT Osteoabsorptiometry (2018)
  • Author(s): Irie Tohru、Takahashi Daisuke、Asano Tsuyoshi、Arai Ryuta、Terkawi Muhammad Alaa、Ito Yoichi M.、Iwasaki Norimasa
  • Journal Title: Clinical Orthopaedics and Related Research Volume: 476 Issue: 7 Pages: 1455-1465
  • DOI: 10.1097/01.blo.0000533619.50951.e3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopedic implants uncovers a common gene expression signature of rheumatoid arthritis (2018)
  • Author(s): Terkawi Mohamad Alaa、Hamasaki Masanari、Takahashi Daisuke、Ota Masahiro、Kadoya Ken、Yutani Tomoyo、Uetsuki Keita、Asano Tsuyoshi、Irie Tohru、Arai Ryuta、Onodera Tomohiro、Takahata Masahiko、Iwasaki Norimasa
  • Journal Title: Acta Biomaterialia Volume: 65 Pages: 417-425
  • DOI: 10.1016/j.actbio.2017.11.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis (2017)
  • Author(s): Tuvshintulga Bumduuren、AbouLaila Mahmoud、Sivakumar Thillaiampalam、Tayebwa Dickson Stuart、Gantuya Sambuu、Naranbaatar Khandsuren、Ishiyama Aki、Iwatsuki Masato、Otoguro Kazuhiko、?mura Satoshi、Terkawi Mohamad Alaa、Guswanto Azirwan、Rizk Mohamed Abdo、Yokoyama Naoaki、Igarashi Ikuo
  • Journal Title: Scientific Report Volume: 7 Issue: 1
  • DOI: 10.1038/s41598-017-14304-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human babesiosis: Indication of a molecular mimicry between thrombospondin domains from a novel Babesia microti BmP53 protein and host platelets molecules (2017)
  • Author(s): Mousa Ahmed Abdelmoniem、Roche Daniel Barry、Terkawi Mohamad Alaa、Kameyama Kyohko、Kamyingkird Ketsarin、Vudriko Patrick、Salama Akram、Cao Shinuo、Orabi Sahar、Khalifa Hanem、Ahmed Mohamed、Attia Mabrouk、Elkirdasy Ahmed、Nishikawa Yoshifumi、Xuan Xuenan、Cornillot Emmanuel
  • Journal Title: Plos One Volume: 12 Issue: 10 Pages: e0185372-e0185372
  • DOI: 10.1371/journal.pone.0185372
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunization with Toxoplasma gondii peroxiredoxin 1 induces protective immunity against toxoplasmosis in mice (2017)
  • Author(s): Fereig Ragab M.、Kuroda Yasuhiro、Terkawi Mohamad Alaa、Mahmoud Motamed Elsayed、Nishikawa Yoshifumi
  • Journal Title: Plos One Volume: 12 Issue: 4 Pages: e0176324-e0176324
  • DOI: 10.1371/journal.pone.0176324
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Neutrophils-derived annexin A1 is a potential regulator of inflammatory osteolysis triggered by polyethylene wear debris of orthopedic implants (2020)
  • Author(s): Hend Alhasan
  • Organizer: Orthopaedic Research Society Annual Meeting ORS 2020
  • Int'l Joint Research
• [Presentation] Macrophage-derived thymidine phosphorylase promotes osteoclastogenesis and bone resorption in inflammatory osteolysis (2019)
  • Author(s): Gen Matsumae
  • Organizer: 13th World Immune Regulation Meeting, 2019
  • Int'l Joint Research
• [Presentation] Macrophage-derived thymidine phosphorylase promotes osteoclastogenesis and bone resorption in inflammatory osteolysis (2019)
  • Author(s): Gen Matsumae
  • Organizer: 46th European Calcified Tissue Society Congress
  • Int'l Joint Research
• [Presentation] A double-edged sword in aseptic loosening of total joint arthroplasty (2019)
  • Author(s): Alaa Terkawi
  • Organizer: Asia Pacific Society for Biology and Medical Sciences (APSBMS)
  • Int'l Joint Research
• [Presentation] Macrophage-secreted factors due to stimulation by implant wear debris promote osteoclast formation and function in bone loss (2018)
  • Author(s): M Alaa Terkawi
  • Organizer: Orthopaedic Research Society Annual Meeting ORS
  • Int'l Joint Research
• [Presentation] Gene profiling of macrophages stimulated with vitamin E-blended polyethylene orthopedic implants debris identifies IL-27 as potent regulator of osteolysis (2018)
  • Author(s): M Alaa Terkawi
  • Organizer: 33rd Annual Research Meeting of the Japanese Orthopaedic Association
• [Presentation] The crucial role of neutrophils in resolution of inflammation elicited by polyethylene debris of orthopedic implants (2018)
  • Author(s): M Alaa Terkawi
  • Organizer: 40th Annual Meeting of the Japanese Society for Biomaterials
• [Presentation] Gene profiling of macrophages stimulated by vitamin E-blended ultra-high molecular weight polyethylene debris of orthopedic implants identifies IL-27 as potent regulator of osteolysis (2018)
  • Author(s): M Alaa Terkawi
  • Organizer: 47th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research
• [Presentation] Transcriptional profile of stimulated macrophages by ultra-high molecular weight polyethylene debris of orthopedic implants implies a novel mechanism of osteolysis (2018)
  • Author(s): M Alaa Terkawi
  • Organizer: 18th Japan-France Orthopedic Society Conference SOFJO
  • Int'l Joint Research
• [Presentation] Macrophage-secreted factors due to stimulation by implant wear debris promote osteoclast formation and function in bone loss (2018)
  • Author(s): Terkawi MA, Hamasaki M, Ota M, Takahashi D, Alhasan H, Takahashi M, Asano T, Irie T, Kadoya K, Iwasaki N.
  • Organizer: 2018 Orthopaedic Research Society meeting
  • Int'l Joint Research
• [Presentation] Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopedic implants reveals a novel mechanism of osteolysis (2018)
  • Author(s): Terkawi MA, Hamasaki M, Ota M, Takahashi D, Alhasan H, Iwasaki N.
  • Organizer: 12th World Immune Regulation Meeting
  • Int'l Joint Research
• [Presentation] Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopaedic implants uncovers a common gene expression signature of rheumatoid arthritis (2017)
  • Author(s): Terkawi MA, Hamasaki M, Takahashi D, Iwasaki N
  • Organizer: The 16th Awaji International Forum of Infection and Immunity
  • Int'l Joint Research
• [Presentation] Transcriptional profile of human macrophages exposed to ultra-high molecular weight polyethylene particles reveals a common gene expression signature of rheumatoid arthritis (2017)
  • Author(s): Terkawi MA, Hamasaki M, Takahashi D, Kadoya K, Asano T, Irie T, Onodera T, Iwasaki N
  • Organizer: The 32nd Annual Research Meeting of the Japanese Orthopaedic Association
• [Presentation] Comparison of gene expression profiles of human macrophages stimulated by conventional and vitamin E-blended ultra-high molecular weight polyethylene particles of orthopedic implants (2017)
  • Author(s): Terkawi MA, Hamasaki M, Takahashi D, Iwasaki N
  • Organizer: The 39th Annual Meeting of the Japanese Society for Biomaterials