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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.
Int Immunopharmacol. 2013 Oct; 17(2):329-35.II

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+Show Affiliations

Department of Emergency Medicine, Zhejiang University, Hangzhou, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23856614

Citation

Zhong, Hui-ming, et al. "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." International Immunopharmacology, vol. 17, no. 2, 2013, pp. 329-35.
Zhong HM, Ding QH, Chen WP, et al. 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. Int Immunopharmacol. 2013;17(2):329-35.
Zhong, H. M., Ding, Q. H., Chen, W. P., & Luo, R. B. (2013). 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. International Immunopharmacology, 17(2), 329-35. https://doi.org/10.1016/j.intimp.2013.06.027
Zhong HM, et al. 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. Int Immunopharmacol. 2013;17(2):329-35. PubMed PMID: 23856614.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zhong,Hui-ming, AU - Ding,Qian-hai, AU - Chen,Wei-ping, AU - Luo,Ru-bin, Y1 - 2013/07/13/ PY - 2013/04/10/received PY - 2013/05/05/revised PY - 2013/06/24/accepted PY - 2013/7/17/entrez PY - 2013/7/17/pubmed PY - 2014/4/23/medline KW - Inducible nitric oxide synthase KW - Matrix metalloproteinase KW - Mitogen activated protein kinases KW - Nuclear factor kappa B KW - Osteoarthritis KW - Vorinostat SP - 329 EP - 35 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 17 IS - 2 N2 - 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. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/23856614/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(13)00279-8 DB - PRIME DP - Unbound Medicine ER -