Takahiro Machida1, Keiichiro Nishida2, Yoshihisa Nasu3, Ryuichi Nakahara4, Masatsugu Ozawa5, Ryozo Harada1, Masahiro Horita1, Ayumu Takeshita1, Daisuke Kaneda1, Aki Yoshida1, Toshifumi Ozaki1. 1. Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. 2. Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. knishida@md.okayama-u.ac.jp. 3. Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. 4. Department of Musculoskeletal Traumatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. 5. Department of Orthopaedic Surgery, Okayama City Hospital, 3-20-1 Kitanagaseomote-cho, Okayama, 700-8557, Japan.
Abstract
OBJECTIVE: To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain (COL2A1), aggrecan (ACAN), ADAMTS4, ADAMTS5, MMP13, and runt-related transcription factor 2 (RUNX-2) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay. RESULTS: COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4, ADAMTS5, MMP13, and RUNX2, and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3. CONCLUSION: Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.
OBJECTIVE: To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain (COL2A1), aggrecan (ACAN), ADAMTS4, ADAMTS5, MMP13, and runt-related transcription factor 2 (RUNX-2) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay. RESULTS:COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4, ADAMTS5, MMP13, and RUNX2, and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3. CONCLUSION:Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.
Authors: Ronald F van Vollenhoven; Roy Fleischmann; Stanley Cohen; Eun Bong Lee; Juan A García Meijide; Sylke Wagner; Sarka Forejtova; Samuel H Zwillich; David Gruben; Tamas Koncz; Gene V Wallenstein; Sriram Krishnaswami; John D Bradley; Bethanie Wilkinson Journal: N Engl J Med Date: 2012-08-09 Impact factor: 91.245
Authors: Michael E Weinblatt; Mark C Genovese; Meilien Ho; Sally Hollis; Krystyna Rosiak-Jedrychowicz; Arthur Kavanaugh; David S Millson; Gustavo Leon; Millie Wang; Désirée van der Heijde Journal: Arthritis Rheumatol Date: 2014-12 Impact factor: 10.995
Authors: M Mohtai; M K Gupta; B Donlon; B Ellison; J Cooke; G Gibbons; D J Schurman; R L Smith Journal: J Orthop Res Date: 1996-01 Impact factor: 3.494
Authors: Vibeke Strand; Joel Kremer; Gene Wallenstein; Keith S Kanik; Carol Connell; David Gruben; Samuel H Zwillich; Roy Fleischmann Journal: Arthritis Res Ther Date: 2015-11-04 Impact factor: 5.156
Authors: Haneen A Abusharkh; Alia H Mallah; Mahmoud M Amr; Juana Mendenhall; Bulent A Gozen; Edwin M Tingstad; Nehal I Abu-Lail; Bernard J Van Wie Journal: In Vitro Cell Dev Biol Anim Date: 2021-06-15 Impact factor: 2.723