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Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment

1
Graduate Institute of Life Science, National Defense Medical Center, Taipei 11490, Taiwan
2
Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Miaoli 35053, Taiwan
3
Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
4
Department of Orthopaedics, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
5
Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan 33305, Taiwan
6
Graduate Institute of Clinical Research, National Defense Medical Center, Taipei 11490, Taiwan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(3), 825; https://doi.org/10.3390/ijms19030825
Received: 10 February 2018 / Revised: 4 March 2018 / Accepted: 9 March 2018 / Published: 12 March 2018
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF))
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Abstract

Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/β-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research. View Full-Text
Keywords: dextromethorphan; osteoarthritis; chondrocyte; MMP-13; collagen-induced arthritis dextromethorphan; osteoarthritis; chondrocyte; MMP-13; collagen-induced arthritis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Chen, L.W.; Liu, F.-C.; Hung, L.-F.; Huang, C.-Y.; Lien, S.-B.; Lin, L.-C.; Lai, J.-H.; Ho, L.-J. Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment. Int. J. Mol. Sci. 2018, 19, 825.

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