Transient receptor potential vanilloid 4 (TRPV4) plays a pivotal role in chondrogenic mechanotransduction in ATDC5 cells

• Project/Area Number: 26670660
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Nagoya University
• Principal Investigator: Naoki Ishiguro 名古屋大学, 医学(系)研究科(研究院), 教授 (20212871)
• Co-Investigator(Kenkyū-buntansha): KITOH HIROSHI 名古屋大学, 医学系研究科, 准教授 (40291174) ; KOJIMA TOSHIHISA 名古屋大学, 医学部附属病院, 講師 (70378032) ; MISHIMA KENICHI 名古屋大学, 医学系研究科, 寄附講座助教 (40646519)
• Co-Investigator(Renkei-kenkyūsha): OHNO KINJI 名古屋大学, 医学系研究科, 教授 (80397455)
• 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: TRPV4 / ATDC5 / SOX9 / 機械的刺激 / RUNX2 / MMP-13

Outline of Final Research Achievements

The study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4) in the response to mechanical stress in chondrogenic cells. Sox9 and AGC mRNA levels were significantly higher in cells after mechanical stress loading compared to cells that were not stretched. Up-regulation of Sox9 mRNA induced by mechanical stress was attenuated by RR and TRPV4 siRNA. A pharmacological activator of TRPV4, 4α-phorbol 12, 13-didecanoate (4αPDD), increased chondrogenesis. The findings suggest that Ca2+ signaling activated by mechanical stress and regulated by TRPV4 promotes chondrogenesis in ATDC5 cells. This suggests that artificial activation of TRPV4 may serve as an intervention for treating osteoarthritis.

Research Products

• [Journal Article] Tranilast stimulates endochondral ossification by upregulating SOX9 and RUNX2 promoters. (2016)
  • Author(s): Hasegawa S, Kitoh H, Ohkawara B, Mishima K, Matsushita M, Masuda A, Ishiguro N, Ohno K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 470(2) Issue: 2 Pages: 356-61
  • DOI: 10.1016/j.bbrc.2016.01.044
  • Peer Reviewed / Open Access
• [Journal Article] Predictive factors for achieving low disease activity at 52 weeks after switching from tumor necrosis factor inhibitors to abatacept: results from a multicenter observational cohort study of Japanese patients (2016)
  • Author(s): Kojima, T., Takahashi, N., Kaneko, A., Kida, D., Hirano, Y., Fujibayashi, T., Yabe, Y., Takagi, H., Oguchi, T., Miyake, H., Kato, T., Watanabe, T., Hayashi, M., Shioura, T., Kanayama, Y., Funahashi, K., Asai, S., Yoshioka, Y., Terabe, K., Takemoto, T., Asai, N., Ishiguro, N.
  • Journal Title: Clinical Rheumatology Volume: 35 Issue: 1 Pages: 219-25
  • DOI: 10.1007/s10067-015-3135-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disease activity early in treatment as a predictor of future low disease activity in RA patients treated with iguratimod. (2016)
  • Author(s): Yoshioka Y, Takahashi N, Kaneko A, Hirano Y, Kanayama Y, Kanda H, Takagi H, Ito T, Kato T, Saito K, Funahashi K, Asai S, Takemoto T, Terabe K, Asai N, Ishiguro N, Kojima T.
  • Journal Title: Mod Rheumatol. Volume: 26(2) Issue: 2 Pages: 169-74
  • DOI: 10.3109/14397595.2015.1069475
  • Peer Reviewed
• [Journal Article] Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis. (2016)
  • Author(s): Ishikawa J, Takahashi N, Matsumoto T, Yoshioka Y, Yamamoto N, Nishikawa M, Hibi H, Ishigro N, Ueda M, Furukawa K, Yamamoto A.
  • Journal Title: Bone. Volume: 83 Pages: 210-219
  • DOI: 10.1016/j.bone.2015.11.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prediction of clinically significant leg-length discrepancy in congenital disorders (2015)
  • Author(s): Mishima K, Kitoh H, Kadono I, Mastushita M, Sugiura H, Hasegawa S, Kitamura A, Nishida Y, Ishiguro N
  • Journal Title: Orthopedics Volume: 38 Issue: 10 Pages: 919-924
  • DOI: 10.3928/01477447-20151002-60
  • Peer Reviewed / Open Access
• [Journal Article] Lansoprazole upregulates polyubiquitination of TRAF6 and facilitates Runx2-mediated osteoblastogenesis (2015)
  • Author(s): Kenichi Mishima, Hiroshi Kitoh, Bisei Ohkawara, Tatsuya Okuno, Mikako Ito, Akio Masuda, Naoki Ishiguro, Kinji Ohno
  • Journal Title: EBio Medicin Volume: 2 Issue: 12 Pages: 20462061-20462061
  • DOI: 10.1016/j.ebiom.2015.11.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Longterm efficacy and safety of abatacept in patients with rheumatoid arthritis treated in routine clinical practice: effect of concomitant methotrexate after 24 weeks. (2015)
  • Author(s): Takahashi N, Kojima T, Kaneko A, Kida D, Hirano Y, Fujibayashi T, Yabe Y, Takagi H, Oguchi T, Miyake H, Kato T, Watanabe T, Hayashi M, Kanayama Y, Funahashi K, Asai S, Yoshioka Y, Takemoto T, Terabe K, Asai N, Ishiguro N.
  • Journal Title: J Rheumatol. Volume: 42(5) Issue: 5 Pages: 786-93
  • DOI: 10.3899/jrheum.141288
  • Peer Reviewed
• [Journal Article] Concomitant methotrexate and tacrolimus augment the clinical response to abatacept in patients with rheumatoid arthritis with a prior history of biological DMARD use. (2015)
  • Author(s): Takahashi N, Fujibayashi T, Kida D, Hirano Y, Kato T, Kato D, Saito K, Kaneko A, Yabe Y, Takagi H, Oguchi T, Miyake H, Watanabe T, Hayashi M, Kanayama Y, Funahashi K, Hanabayashi M, Hirabara S, Asai S, Takemoto T, Terabe K, Asai N, Yoshioka Y, Ishiguro N, Kojima T.
  • Journal Title: Rheumatol Int. Volume: 35(10) Issue: 10 Pages: 1707-16
  • DOI: 10.1007/s00296-015-3283-4
  • Peer Reviewed
• [Journal Article] Effects of Concomitant Methotrexate on Large Joint Replacement in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: A Multicenter Retrospective Cohort Study in Japan. (2015)
  • Author(s): Asai S, Kojima T, Oguchi T, Kaneko A, Hirano Y, Yabe Y, Kanayama Y, Takahashi N, Funahashi K, Hanabayashi M, Hirabara S, Yoshioka Y, Takemoto T, Terabe K, Asai N, Ishiguro N.
  • Journal Title: Arthritis Care Res (Hoboken). Volume: 67(10) Issue: 10 Pages: 1363-70
  • DOI: 10.1002/acr.22596
  • Peer Reviewed
• [Journal Article] Use of a 12-week observational period for predicting low disease activity at 52 weeks in RA patients treated with abatacept: a retrospective observational study based on data from a Japanese multicentre registry study. (2015)
  • Author(s): Takahashi N, Kojima T, Kaneko A, Kida D, Hirano Y, Fujibayashi T, Yabe Y, Takagi H, Oguchi T, Miyake H, Kato T, Fukaya N, Hayashi M, Tsuboi S, Kanayama Y, Funahashi K, Hanabayashi M, Hirabara S, Asai S, Yoshioka Y, Ishiguro N
  • Journal Title: Rheumatology (Oxford) Volume: 54(5) Issue: 5 Pages: 854-859
  • DOI: 10.1093/rheumatology/keu418
  • Peer Reviewed
• [Journal Article] Concomitant Methotrexate Protects Against Total Knee Arthroplasty in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors. (2015)
  • Author(s): Asai S, Takahashi N, Funahashi K, Yoshioka Y, Takemoto T, Terabe K, Asai N, Ishiguro N, Kojima T.
  • Journal Title: J Rheumatol. Volume: 42(12) Issue: 12 Pages: 2255-60
  • DOI: 10.3899/jrheum.150410
  • Peer Reviewed
• [Journal Article] High incidence of regional and in-transit lymph node metastasis in patients with alveolar rhabdomyosarcoma. (2014)
  • Author(s): Nishida Y, Tsukushi S, Urakawa H, Sugiura H, Nakashima H, Yamada Y, Ishiguro N.
  • Journal Title: Int J Clin Oncol Volume: 19(3) Issue: 3 Pages: 536-43
  • DOI: 10.1007/s10147-013-0571-4
  • Peer Reviewed / Open Access
• [Journal Article] Hyaluronan expression as a significant prognostic factor in patients with ma lignant peripheral nerve sheath tumors. (2014)
  • Author(s): Ikuta K, Urakawa H, Kozawa E, Arai E, Zhuo L, Futamura N, Hamada S, Kimata K, Ishiguro N, Nishida Y.
  • Journal Title: Clin Exp Metastasis Volume: 31 Issue: 6 Pages: 715-725
  • DOI: 10.1007/s10585-014-9662-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Early and late fracture following extensive limb lengthening in achondroplasia and hypochondroplasia. (2014)
  • Author(s): Kitoh H, Kaneko H, Mishima K, Matsushita M, Kadono I, Nishida Y, Ishiguro N.
  • Journal Title: Bone Joint J Volume: 96-B(9) Issue: 9 Pages: 1269-1273
  • DOI: 10.1302/0301-620x.96b9.33840
  • Peer Reviewed / Open Access
• [Journal Article] Radiographic characteristics of the hand and cervical spine in fibrodysplasia ossificans progressiva (2014)
  • Author(s): Mishima K, Kitoh H, Haga N, Nakashima Y, Kamizono J, Katagiri T, Susami T, Matsushita M, Ishiguro N.
  • Journal Title: Intractable & Rare Diseases Research Volume: 3 Issue: 2 Pages: 46-51
  • DOI: 10.5582/irdr.2014.01009
  • NAID: 130005008088
  • ISSN: 2186-361X, 2186-3644
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy. (2014)
  • Author(s): Hoover-Fong J, Sobreira N, Jurgens J, Modaff P, Blout C, Moser A, Kim OH, Cho TJ, Cho SY, Kim SJ, Jin DK, Kitoh H, Park WY, Ling H, Hetrick KN, Doheny KF, Valle D, Pauli RM.
  • Journal Title: Am J Hum Genet Volume: 94(1) Issue: 1 Pages: 105-112
  • DOI: 10.1016/j.ajhg.2013.11.018
  • Peer Reviewed / Open Access
• [Journal Article] Benign prenatal hypophosphatasia: a treatable disease not to be missed. (2014)
  • Author(s): Matsushita M, Kitoh H, Michigami T, Tachikawa K, Kaneko H, Mishima K, Ishiguro N.
  • Journal Title: Ped Radiol Volume: 44(3) Issue: 3 Pages: 340-343
  • DOI: 10.1007/s00247-013-2805-z
  • Peer Reviewed / Open Access
• [Journal Article] 骨形成促進効果を有する既存薬の同定とその臨床応用の可能性 (2014)
  • Author(s): 三島 健一、鬼頭 浩史、金子 浩史、松下 雅樹、石黒 直樹
  • Journal Title: 日本小児整形外科学会雑誌 Volume: 22(2) Pages: 374-378
• [Journal Article] A novel in-frame deletion of the RUNX2 gene causes a classic form of cleidocranial dysplasia (2013)
  • Author(s): Mastushita M., Kitoh H., Kaneko H., Mishima K., Itoh Y., Tokita Y., Ishiguro N.
  • Journal Title: J Bone Miner Metab Volume: 未定 Issue: 1 Pages: 96-99
  • DOI: 10.1007/s00774-013-0456-7
  • Peer Reviewed / Open Access
• [Presentation] The Mechanical Stress Loading Can Induce The Fragmetation Of Cd44 by increased ADAM-10 expression In A Chondrocyte Cell Line. (2016)
  • Author(s): Kobayakawa T, Takahashi N, Kojima T, Ishiguro N
  • Organizer: Orthopaedic Research Society
  • Place of Presentation: オーランド,アメリカ
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] ADAM10 inhibitor suppresses chondrogenic dedifferentiation in bovine primary chondrocyte cells. (2016)
  • Author(s): Sobue Y, Kojima T, Takahashi N, Ishiguro N
  • Organizer: Orthopaedic Research Society
  • Place of Presentation: オーランド,アメリカ
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] Lansoprazole regulates osteoclast formation and function. (2016)
  • Author(s): Mishima K, Kitoh H, Matsushita M, Sugiura H, Hasegawa S, Ishiguro N
  • Organizer: Orthopaedic Research Society
  • Place of Presentation: オーランド,アメリカ
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] Radical Therapeutic Strategy For Foramen Magnum Stenosis And Spinal Canal Stenosis In Achondroplasia. (2016)
  • Author(s): Matsushita M, Kitoh H, Mishima K, Sugiura H, Hasegawa S, Ishiguro N, Ohno K
  • Organizer: Orthopaedic Research Society
  • Place of Presentation: オーランド,アメリカ
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] 関節リウマチの手術療法Update (2015)
  • Author(s): 石黒直樹
  • Organizer: 第30回日本臨床リウマチ学会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-11-21
  • Invited
• [Presentation] Predictive Factors for Achieving Low Disease Activity at 52 Weeks after Switching from Tumor Necrosis Factor Inhibitors to Abatacept: Results from a Multicenter Observational Cohort Study of Japanese Patients. (2015)
  • Author(s): Kojima T, Takahashi N, Kaneko A, Kida D, Hirano Y, Fujibayashi T, Yabe Y, Takagi H, Oguchi T, Miyake H, Kato T, Watanabe T, Hayashi M, Shioura T, Kanayama Y, Funahashi K, Asai S, Yoshioka Y, Terabe K, Takemoto T, Asai N, Ishiguro N
  • Organizer: American College of Rheumatology
  • Place of Presentation: サンフランシスコ,アメリカ
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Relationship between index of activity speed (Time Up and Go test) and patient-reported outcome in patients with long-standing rheumatoid arthritis : multicenter prospective cohort study for evaluation of joint surgery on physical function (2015)
  • Author(s): Kojima T, Ishikawa H, Nishida K, Hashimoto J, Miyahara H, Tanaka S, Haga N, Niki Y, Kojima M, Ishiguro N
  • Organizer: American College of Rheumatology
  • Place of Presentation: サンフランシスコ,アメリカ
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] 軟骨細胞におけるSOX9発現を促進させる既存薬の検索 (2015)
  • Author(s): 長谷川幸,鬼頭浩史,三島健一,松下雅樹,杉浦洋,北村暁子,西田佳弘,石黒直樹,大野欽司
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場、ＡＮＡクラウンプラザホテル富山、富山市民プラザ（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] Meclozineは軟骨無形成症における大後頭孔および脊柱管狭窄を改善しうる (2015)
  • Author(s): 松下雅樹,鬼頭浩史,三島健一,杉浦洋,長谷川幸,北村暁子,西田佳弘,石黒直樹,大野欽司
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場、ＡＮＡクラウンプラザホテル富山、富山市民プラザ（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 骨芽細胞におけるFGF23の発現を抑制する既存薬の検索 (2015)
  • Author(s): 杉浦洋,鬼頭浩史,三島健一,松下雅樹,長谷川幸,北村暁子,大河原美静,西田佳弘,石黒直樹,大野欽司
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場、ＡＮＡクラウンプラザホテル富山、富山市民プラザ（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 軟骨無形成症における根本的治療薬の開発 (2015)
  • Author(s): 松下雅樹,鬼頭浩史,三島健一,杉浦洋,長谷川幸,北村暁子,西田佳弘,石黒直樹,大野欽司
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場、ＡＮＡクラウンプラザホテル富山、富山市民プラザ（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 先天性股関節脱臼（ＤＤＨ）に対するリューメンビューゲル（ＲＢ）法の治療成績不良因子の検討 (2015)
  • Author(s): 三島健一,鬼頭浩史,松下雅樹,門野泉,杉浦洋,長谷川幸,北村暁子,西田佳弘,石黒直樹
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] 骨系統疾患の診断と治療－わが国の現状と展望－ (2015)
  • Author(s): 鬼頭浩史,三島健一,松下雅樹,杉浦洋,長谷川幸,北村暁子,石黒直樹
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] ランソプラゾールによる骨形成促進効果の解析 (2015)
  • Author(s): 三島健一,鬼頭浩史,杉浦洋,松下雅樹,長谷川幸,北村暁子,門野泉,西田佳弘,石黒直樹
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] 発育性股関節形成不全に対するSalter骨盤骨切り術の成績不良因子：対側股関節の潜在性形成不全は成績に影響するか (2015)
  • Author(s): 鬼頭浩史,岩田浩志,大石央代,松村明日香,服部義,石黒直樹
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] 当科における鏡視下Bankart修復術の術後成績と影響を与える因子の統計学的検討 (2015)
  • Author(s): 酒井忠博，平岩秀樹，濱田恭，小田智之，高松晃，宮本健太郎，岸本烈純，土谷早穂，石黒直樹
  • Organizer: 第88回日本整形外科学会学術総会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際会議場、神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-05-21
• [Presentation] 【抗リウマチ薬市販後調査の報告】 「イグラチモド」 (2015)
  • Author(s): 石黒直樹
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-23
  • Invited
• [Presentation] 関節リウマチ治療のピットフォール (2015)
  • Author(s): 石黒直樹
  • Organizer: 第124回中部日本整形外科災害外科学会
  • Place of Presentation: ホテル日航金沢（石川県金沢市）
  • Year and Date: 2015-04-10
  • Invited
• [Presentation] Meclozine enhances skeletal growth in transgenic achondroplasia mice with a constitutive active FGFR3 mutation (2015)
  • Author(s): Matsushita, Masaki; Kitoh, Hiroshi; Kenichi Mishima; Ishiguro Naoki; Ohno Kinji
  • Organizer: 2015 Annual Meeting - Orthopaedic Research Society
  • Place of Presentation: Las Vegas(USA)
  • Year and Date: 2015-03-28 – 2015-03-31
• [Presentation] Wnt/β-カテニンシグナル制御を介した変形性関節症治療薬の探索 (2015)
  • Author(s): 宮本健太郎、大河原美静、酒井忠博、高松晃、石黒直樹、大野欽司
  • Organizer: 第28回日本軟骨代謝学会
  • Place of Presentation: 東京医科歯科大学（東京都文京区）
  • Year and Date: 2015-03-06 – 2015-03-07
• [Presentation] meclozineはオフラベル効能によりFGFR3シグナルを抑制し軟骨無形成症の根本的治療薬となりうる (2015)
  • Author(s): 松下 雅樹、 鬼頭 浩史、 三島 健一、西田 佳弘、石黒 直樹、 大野 欽司
  • Organizer: 第28回日本軟骨代謝学会
  • Place of Presentation: 東京医科歯科大学（東京都文京区）
  • Year and Date: 2015-03-06 – 2015-03-07
• [Presentation] 乗り物酔い止めOTC薬meclozineはFGFR3シグナルを抑制して軟骨無形成症の低身長をレスキューする (2014)
  • Author(s): 松下 雅樹、 鬼頭 浩史、 三島 健一、石黒 直樹、 大野 欽司
  • Organizer: 第32回小児代謝性骨疾患研究会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2014-12-06
• [Presentation] PRPゲルを用いた自家培養軟骨細胞移植術（PRP-ACI) (2014)
  • Author(s): 酒井忠博、平岩秀樹、濱田恭、石黒直樹
  • Organizer: 第42回日本関節病学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2014-11-06 – 2014-11-07
• [Presentation] 関節軟骨細胞におけるＣＤ４４の断片化とその意義について (2014)
  • Author(s): 高橋伸典、寺部健哉、Cheryl B. Knudson、Warren Knudson、小嶋俊久、石黒直樹
  • Organizer: 第46回日本結合組織学会学術大会
  • Place of Presentation: ウインクあいち（愛知県名古屋市）
  • Year and Date: 2014-06-05 – 2014-06-07