期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 17, 期 2, 页码 329-335出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2013.06.027
关键词
Vorinostat; Inducible nitric oxide synthase; Matrix metalloproteinase; Nuclear factor kappa B; Mitogen activated protein kinases; Osteoarthritis
资金
- National Natural Science Foundation of China [81201429]
Overproduction of nitric oxide (NO) and matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). In present study, we investigated whether vorinostat can inhibit the catabolic effects of IL-1 beta in vitro, especially the inhibition of MMPs and inducible nitric oxide synthase (iNOS) through the attenuation of nuclear factor kappa-B (NF-kappa B) and mitogen activated protein kinase (MAPK) pathways in human chondrocytes. Human OA chondrocytes were either left untreated or treated with various concentrations of vorinostat followed by incubation with IL-1 beta (5 ng/mL). Effects of vorinostat on IL-1 beta-induced gene and protein expression of iNOS, MMP-1, MMP-13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) were verified by quantitative real time-PCR and Western blot analysis. Production of NO, MMP-1, MMP-13 and TIMP-1 released in culture supernatant was estimated using commercially available kits. The roles of NF-kappa B and MAPK pathways in the regulation of targeted genes and the mechanism involved in vorinostat mediated modulation of these genes were determined by Western blot using specific antibodies. We found that vorinostat down-regulated iNOS, MMP-1 and MMP-13 expression and up-regulated TIMP-1 expression in human OA chondrocytes. In addition, the release of NO, MMP-1 and MMP-13 secreted from IL-1 beta stimulated chondrocytes was also suppressed by vorinostat Interestingly, vorinostat selectively inhibited IL-1 beta-induced p38 and ERK1/2 activation without affecting JNK activation. Furthermore, we observed that vorinostat inhibited NF-kappa B pathway by suppressing the degradation of I-kappa B alpha and attenuating NF-kappa B p65 translocation to the nucleus. These results suggest that vorinostat may be a promising therapeutic agent for the prevention and treatment of OA. (C) 2013 Elsevier B.V. All rights reserved.
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