Establishment of treatment strategy against osteoarthritis targeting transcription factor Nkx3.2

• Project/Area Number: 26861189
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Osaka University
• Principal Investigator: Ebina Kosuke 大阪大学, 医学(系)研究科(研究院), 助教 (70612076)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 軟骨再生 / 滑膜細胞 / 変形性関節症 / 関節リウマチ / 同種移植 / 細胞バンク / 同種細胞移植 / 遺伝子導入

Outline of Final Research Achievements

We confirmed that gene expression of Nkx3.2 is down-regulated in degenerated cartilage compared to intact cartilage of osteoarthritis patients. We developed scaffold-free tissue engineering construct (TEC) from synovial mesenchymal stem cells (SMSCs) which repairs cartilage defect. We also developed Nkx3.2 gene inserted plasmid, and transfected into synovial MSCs, which showed 90-30000 folds overexpression of Nkx3.2 gene and 2-7 folds of Sox9 gene. Finally, we induced chondrogenic differentiation to this Nkx3.2 gene overexpressed synovial MSCs, while failed to confirm significant increase in size and extra-cellular matrix production. Then, we tried to establish allogenic SMSCs bank to overcome the disadvantage of autogenic transplantation. We investigated that SMSCs from osteoarthritis and rheumatoid arthritis patients exhibit good potential to repair the osteochondral defects of nude rat, indicating the possibility of promising cell sources for cartilage repair.

Research Products

• [Journal Article] Synovial mesenchymal stem cells from osteo- or rheumatoid arthritis joints exhibit good potential for cartilage repair using a scaffold-free tissue engineering approach. (2016)
  • Author(s): Koizumi K, Ebina K, Hart DA, Hirao M, Noguchi T, Sugita N, Yasui Y, Chijimatsu R, Yoshikawa H, Nakamura N.
  • Journal Title: Osteoarthritis Cartilage Volume: Mar 10 Issue: 8 Pages: 1413-1422
  • DOI: 10.1016/j.joca.2016.03.006
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis. (2016)
  • Author(s): Ebina K, Hashimoto J, Kashii M, Hirao M, Kaneshiro S, Noguchi T, Tsukamoto Y, Yoshikawa H.
  • Journal Title: J Bone Miner Metab Volume: Jan 13
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The efficacy and safety of additional administration of tacrolimus in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab. (2016)
  • Author(s): Shoichi Kaneshiro, Kosuke Ebina, Makoto Hirao, Hideki Tsuboi, Masataka Nishikawa, Akihide Nampei, Yoshio Nagayama, Koichiro Takahi, Takaaki Noguchi, Hajime Owaki, Jun Hashimoto, Hideki Yoshikawa.
  • Journal Title: Mod Rheumatol Volume: In Press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hallux valgus deformity after total ankle arthroplasty for rheumatoid arthritis: a case report. (2016)
  • Author(s): Makoto Hirao, Yukio Hirai, Kosuke Ebina, Kenrin Shi, Takaaki Noguchi, Hideki Tsuboi, Jun Hashimoto, Hideki Yoshikawa.
  • Journal Title: Mod Rheumatol Volume: In Press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of switching weekly alendronate or risedronate to monthly minodronate in patients with rheumatoid arthritis: a 12-month prospective study. (2015)
  • Author(s): Ebina K, Noguchi T, Hirao M, Hashimoto J, Kaneshiro S, Yukioka M, Yoshikawa H.
  • Journal Title: Osteoporos Int Volume: Oct 16
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Multiple subcutaneous xanthogranuloma at juxta-articular sites with bone cystic changes resembling rheumatoid arthritis: A case report. (2015)
  • Author(s): Kaneshiro S, Shi K, Ebina K, Yukioka M, Yoshikawa H, Murata N.
  • Journal Title: Mod Rheumatol Volume: Dec 23:1-4.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of the effects of 12 months of monthly minodronate monotherapy and monthly minodronate combination therapy with vitamin K2 or eldecalcitol in patients with primary osteoporosis. (2015)
  • Author(s): Ebina K, Noguchi T, Hirao M, Kaneshiro S, Tsukamoto Y, Yoshikawa H.
  • Journal Title: J Bone Miner Metab Volume: Aug 25
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Progranulin plays crucial roles in preserving bone mass by inhibiting TNF-α-induced osteoclastogenesis and promoting osteoblastic differentiation in mice. (2015)
  • Author(s): Noguchi T, Ebina K, Hirao M, Kawase R, Ohama T, Yamashita S, Morimoto T, Koizumi K, Kitaguchi K, Matsuoka H, Kaneshiro S, Yoshikawa H.
  • Journal Title: Biochem Biophys Res Commun Volume: 465(3) Issue: 3 Pages: 638-43
  • DOI: 10.1016/j.bbrc.2015.08.077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine. (2015)
  • Author(s): Kashii M, Matuso Y, Sugiura T, Fujimori T, Nagamoto Y, Makino T, Kaito T, Ebina K, Iwasaki M, Yoshikawa H.
  • Journal Title: J Bone Miner Metab Volume: Jun 4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 1.Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production: Pathogenic and therapeutic implications (2015)
  • Author(s): Yoshida Y, Ogata A, Kang S, Ebina K, Shi K, Nojima S, Kimura T, Ito D, Morimoto K, Nishide M, Hosokawa T, Hirano T, Shima Y, Narazaki M, Tsuboi H, Saeki Y, Tomita T, Tanaka T, Kumanogoh A.
  • Journal Title: Arthritis Rheumatol Volume: none Issue: 6 Pages: 1481-1490
  • DOI: 10.1002/art.39086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 3.Undercarboxylated osteocalcin may be an attractive marker of teriparatide treatment in RA patients: response to Mokuda (2015)
  • Author(s): Ebina K, Hashimoto J, Shi K, Kashii M, Hirao M, Yoshikawa H.
  • Journal Title: Osteoporosis International Volume: 26 Issue: 4 Pages: 1445-1445
  • DOI: 10.1007/s00198-014-2993-x
  • Peer Reviewed
• [Journal Article] Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation. (2015)
  • Author(s): Kaneshiro S, Ebina K, Shi K, Yoshida K, Otsuki D, Yoshikawa H, Higuchi C.
  • Journal Title: J Bone Miner Metab. Volume: 33 Issue: 5 Pages: 486-495
  • DOI: 10.1007/s00774-014-0612-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of adolescent giant parathyroid adenoma presenting multiple osteolytic fractures and postoperative hungry bone syndrome. (2015)
  • Author(s): Ebina K, Miyoshi Y, Izumi S, Hashimoto J, Naka N, Tsukamoto Y, Kashii M, Kaito T, Yoshikawa H.
  • Journal Title: Clin Case Rep Volume: 3(10) Issue: 10 Pages: 835-40
  • DOI: 10.1002/ccr3.360
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 2.Comparison of the effect of 18-month daily teriparatide administration on patients with rheumatoid arthritis and postmenopausal osteoporosis patients (2014)
  • Author(s): Ebina K, Hashimoto J, Shi K, Kashii M, Hirao M, Yoshikawa H.
  • Journal Title: Osteoporosis International Volume: 25 Issue: 12 Pages: 2755-65
  • DOI: 10.1007/s00198-014-2819-x
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation (2014)
  • Author(s): Shoichi Kaneshiro, Kosuke Ebina, Kenrin Shi, Kiyoshi Yoshida, Dai Otsuki, Hideki Yoshikawa, Chikahisa Higuchi.
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: none
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility (2014)
  • Author(s): Jin H, Arase N, Hirayasu K, Kohyama M, Suenaga T, Saito F, Tanimura K, Matsuoka S, Ebina K, Shi K, Toyama-Sorimachi N, Yasuda S, Horita T, Hiwa R, Takasugi K, Ohmura K, Yoshikawa H, Saito T, Atsumi T, Sasazuki T, Katayama I, Lanier LL, Arase H
  • Journal Title: Proceedings of National Academy of Science USA Volume: 111 Issue: 10 Pages: 3787-3792
  • DOI: 10.1073/pnas.1401105111
  • Peer Reviewed / Open Access
• [Presentation] Synovial mesenchymal stem cells from osteoarthritis and rheumatoid arthritis patients exhibit good potential for the development of scaffold-free tissue engineering constructs for cartilage repair. (2016)
  • Author(s): Ebina K, Koizumi K, Hirao M, et al.
  • Organizer: Japan College of Rheumatology 2015 Annual Meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2016-04-21
  • Int'l Joint Research
• [Presentation] Assessment of the Effect of 12 Months Administration of Denosumab in Patients with Rheumatic Diseases. (2015)
  • Author(s): Ebina K, Hashimoto J, Hirao M, et al.
  • Organizer: American College of Rheumatology 2015 Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Cartilage repair ability of scaffold-free tissue engineered construct derived from osteoarthritis and rheumatoid arthritis patients’ synovial mesenchymal stem cells. (2015)
  • Author(s): Koizumi K, Ebina K, Hirao M, et al.
  • Organizer: ASBMR 2015 Annual Meeting
  • Place of Presentation: Seattle,USA
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Apolipoprotein E (ApoE) plays a crucial role in maintaining trabecular and cortical bone mass by promoting osteoblastic differentiation via ERK1/2 pathway and suppressing osteoclast differentiation by down-regulation of c-Fos and NFATc1. (2015)
  • Author(s): Noguchi T, Ebina K, Hirao M, et al.
  • Organizer: ASBMR 2015 Annual Meeting
  • Place of Presentation: Seattle,USA
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] テリパラチド連日製剤投与終了後の骨吸収亢進状態に対するビスフォスフォネートとデノスマブによる骨吸収抑制効果の比較検討 (2015)
  • Author(s): 蛯名耕介, 野口貴明, 平尾眞ら
  • Organizer: 第33回日本骨代謝学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-23
  • Int'l Joint Research
• [Presentation] Assessment of the effect of 12 months administration of denosumab in patients with rheumatic diseases. (2015)
  • Author(s): Ebina K, Hashimoto J, Hirao M, et al.
  • Organizer: 2015 Annual European Congress of Rheumatology - European League Against Rheumatism
  • Place of Presentation: Rome,Italy
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] 閉経後・男性骨粗鬆症患者に対する12か月間のミノドロネート単剤・エルデカルシドール併用・ビタミンK2併用療法の治療効果の比較検討 (2015)
  • Author(s): 蛯名耕介, 野口貴明, 平尾眞ら
  • Organizer: 第88回日本整形外科学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-05-21
  • Int'l Joint Research
• [Presentation] テリパラチド投与後の骨吸収亢進に対する6か月間のビスフォスフォネートとデノスマブ投与効果と長期ビスフォスフォネート投与後の6か月間のデノスマブ投与効果の比較検討 (2014)
  • Author(s): 蛯名 耕介
  • Organizer: 日本骨粗鬆症学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-23 – 2014-10-25
• [Presentation] Comparison of the effect of 18-months daily Teriparatide administration between rheumatoid arthritis and postmenopausal osteoporosis patients (2014)
  • Author(s): 蛯名 耕介
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-24 – 2014-07-26
• [Presentation] Assessment of Time-Dependent Coronal Laxity in Deep Knee Flexion After Posterior-Stabilized Total Knee Arthroplasty (2014)
  • Author(s): 蛯名 耕介
  • Organizer: InternationalCongress for Joint Reconstruction
  • Place of Presentation: Hawaii (USA)
  • Year and Date: 2014-07-16 – 2014-07-19
• [Presentation] 関節リウマチ患者の前足部術式による歩行時荷重分布の違いについての解析 －中足骨頭の温存が荷重分布に及ぼす影響について－ (2014)
  • Author(s): 蛯名 耕介
  • Organizer: 日本整形外科学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2014-05-22 – 2014-05-25
• [Presentation] Comparison of the effect of 12 months administration of Minodronate monotherapy and vitamin K2 or eldecalcitol combination therapy in postmenopausal, male, and RA osteoporosis (2014)
  • Author(s): 蛯名 耕介
  • Organizer: 日本リウマチ学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26