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Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1.
J Pharmacol Exp Ther 2003; 305(3):981-8JP

Abstract

Cytokine-mediated induction and overexpression of matrix metalloproteinases (MMPs) is recognized as an important factor in the pathogenesis of arthritis. Interleukin (IL)-1 beta is a proinflammatory cytokine that is known to superinduce the expression and production of MMP-13 in many cell types. Phenyl N-tert-butylnitrone (PBN), a spin trap agent, inhibited the IL-1 beta-induced expression of MMP-13 in human osteoarthritis (OA) chondrocytes. Down-regulation of MMP-13 expression correlated with the inhibition of mitogen-activated protein kinase (MAPK) subgroups c-Jun NH2-terminal kinase (JNK) and p38-MAPK activation, accumulation of phospho-c-jun, and the DNA binding activity of activating protein-1 (AP-1). Results of in vitro kinase assays showed that exogenously added PBN completely blocked the c-Jun phosphorylating activity of JNK. Interestingly, using in vitro kinase assay, we also found that chondrocyte p38-MAPK phosphorylate c-Jun and that PBN was not very effective in inhibiting c-Jun phosphorylating activity of p38-MAPK. In addition, PBN did not block the ATF-2 phosphorylating activity of p38-MAPK and Elk-1 phosphorylating activity of extracellular regulated kinase p44/p42 in vitro, indicating that PBN may act selectively to inhibit the phosphorylation of c-Jun in OA chondrocytes. Together, our results for the first time demonstrate that PBN suppresses the IL-1 beta-stimulated expression of MMP-13 in OA chondrocytes and that this was achieved by inhibiting the activation of JNK and AP-1. These results suggest that use of PBN or compounds derived from it may be of potential benefit in inhibiting signaling events associated with cartilage degradation in arthritis.

Authors+Show Affiliations

Department of Orthopedics, Case Western Reserve University, Cleveland, OH 44106-4946, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12626640

Citation

Ahmed, Salahuddin, et al. "Phenyl N-tert-butylnitrone Down-regulates Interleukin-1 Beta-stimulated Matrix Metalloproteinase-13 Gene Expression in Human Chondrocytes: Suppression of c-Jun NH2-terminal Kinase, P38-mitogen-activated Protein Kinase and Activating Protein-1." The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 3, 2003, pp. 981-8.
Ahmed S, Rahman A, Hasnain A, et al. Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1. J Pharmacol Exp Ther. 2003;305(3):981-8.
Ahmed, S., Rahman, A., Hasnain, A., Goldberg, V. M., & Haqqi, T. M. (2003). Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1. The Journal of Pharmacology and Experimental Therapeutics, 305(3), pp. 981-8.
Ahmed S, et al. Phenyl N-tert-butylnitrone Down-regulates Interleukin-1 Beta-stimulated Matrix Metalloproteinase-13 Gene Expression in Human Chondrocytes: Suppression of c-Jun NH2-terminal Kinase, P38-mitogen-activated Protein Kinase and Activating Protein-1. J Pharmacol Exp Ther. 2003;305(3):981-8. PubMed PMID: 12626640.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1. AU - Ahmed,Salahuddin, AU - Rahman,Ayesha, AU - Hasnain,Absarul, AU - Goldberg,Victor M, AU - Haqqi,Tariq M, Y1 - 2003/03/06/ PY - 2003/3/11/pubmed PY - 2003/7/8/medline PY - 2003/3/11/entrez SP - 981 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 305 IS - 3 N2 - Cytokine-mediated induction and overexpression of matrix metalloproteinases (MMPs) is recognized as an important factor in the pathogenesis of arthritis. Interleukin (IL)-1 beta is a proinflammatory cytokine that is known to superinduce the expression and production of MMP-13 in many cell types. Phenyl N-tert-butylnitrone (PBN), a spin trap agent, inhibited the IL-1 beta-induced expression of MMP-13 in human osteoarthritis (OA) chondrocytes. Down-regulation of MMP-13 expression correlated with the inhibition of mitogen-activated protein kinase (MAPK) subgroups c-Jun NH2-terminal kinase (JNK) and p38-MAPK activation, accumulation of phospho-c-jun, and the DNA binding activity of activating protein-1 (AP-1). Results of in vitro kinase assays showed that exogenously added PBN completely blocked the c-Jun phosphorylating activity of JNK. Interestingly, using in vitro kinase assay, we also found that chondrocyte p38-MAPK phosphorylate c-Jun and that PBN was not very effective in inhibiting c-Jun phosphorylating activity of p38-MAPK. In addition, PBN did not block the ATF-2 phosphorylating activity of p38-MAPK and Elk-1 phosphorylating activity of extracellular regulated kinase p44/p42 in vitro, indicating that PBN may act selectively to inhibit the phosphorylation of c-Jun in OA chondrocytes. Together, our results for the first time demonstrate that PBN suppresses the IL-1 beta-stimulated expression of MMP-13 in OA chondrocytes and that this was achieved by inhibiting the activation of JNK and AP-1. These results suggest that use of PBN or compounds derived from it may be of potential benefit in inhibiting signaling events associated with cartilage degradation in arthritis. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12626640/Phenyl_N_tert_butylnitrone_down_regulates_interleukin_1_beta_stimulated_matrix_metalloproteinase_13_gene_expression_in_human_chondrocytes:_suppression_of_c_Jun_NH2_terminal_kinase_p38_mitogen_activated_protein_kinase_and_activating_protein_1_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12626640 DB - PRIME DP - Unbound Medicine ER -