title: Vorinostat, a HDAC inhibitor, showed anti-osteoarthritic activities through inhibition of iNOS and MMP expression, p38 and ERK phosphorylation and blocking NF-κB nuclear translocation.
abstract: 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-1β in vitro, especially the inhibition of MMPs and inducible nitric oxide synthase (iNOS) through the attenuation of nuclear factor kappa-B (NF-κB) 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-1β (5ng/mL). Effects of vorinostat on IL-1β-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-κB 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-1β stimulated chondrocytes was also suppressed by vorinostat. Interestingly, vorinostat selectively inhibited IL-1β-induced p38 and ERK1/2 activation without affecting JNK activation. Furthermore, we observed that vorinostat inhibited NF-κB pathway by suppressing the degradation of I-κBα and attenuating NF-κB p65 translocation to the nucleus. These results suggest that vorinostat may be a promising therapeutic agent for the prevention and treatment of OA.
authors.affiliation: Department of Emergency Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Hui-ming
authors.initials: HM
authors.lastname: Zhong
authors.forename: Qian-hai
authors.initials: QH
authors.lastname: Ding
authors.forename: Wei-ping
authors.initials: WP
authors.lastname: Chen
authors.forename: Ru-bin
authors.initials: RB
authors.lastname: Luo
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000368:Aged; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy* / Q000276:immunology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D000077337:Vorinostat; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D016328:NF-kappa B; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077337:Vorinostat; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1
keywords: Inducible nitric oxide synthase; Matrix metalloproteinase; Mitogen activated protein kinases; Nuclear factor kappa B; Osteoarthritis; Vorinostat