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Interleukin-1 induction of aggrecanase gene expression in human articular chondrocytes is mediated by mitogen-activated protein kinases.
Cell Physiol Biochem. 2012; 30(3):563-74.CP

Abstract

BACKGROUND/AIMS

We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And Metalloproteinase with ThromboSpondin motifs) in human articular chondrocytes, a model mimicking human arthritis.

METHODS

Chondrocytes were pretreated with various pharmacological inhibitors and then stimulated with IL-1β for 24 h. ADAMTS-4 expression or activity was studied by RT-PCR or ELISA and other proteins measured by Western blotting.

RESULTS

MAP kinase kinase-specific inhibitor, U0126 inhibited IL-1-induced phosphorylation of ERK1/2 and down-regulated ADAMTS-4 expression and activity. Protein 38 inhibitor, SB203580 down-regulated the phosphorylation of p38 and its target, activating transcription factor-2 (ATF-2), ADAMTS-4 mRNA and activity. C-Jun N-terminal kinase (JNK) inhibitor, SP600125 diminished IL-1-stimulated JNK phosphorylation, ADAMTS-4 mRNA expression and enzyme activity. A c-fos/lipoxygenase pathway inhibitor and antioxidant, nordihydroguaiaretic acid (NDGA) significantly suppressed ADAMTS-4 mRNA induction and activity. Activating protein (AP-1) and nuclear factor kappa B (NF-ĸB) transcription factor inhibitors, curcumin and pyrrolidine dithiocarbamate (PDTC) partially inhibited ADAMTS-4 induction and activity.

CONCLUSION

These results suggest partial involvement of ERK-, p38-and JNK-MAPKs as well as AP-1, ATF-2 and NF-ĸB transcription factors in IL-1-induced ADAMTS-4 in chondrocytes. Inhibition of these targets by the specific pharmacological agents could be useful for reducing aggrecanase-driven cartilage resorption in arthritis.

Authors+Show Affiliations

Département de Médecine, Université de Montréal and Centre de recherche du CHUM (CRCHUM)-Hôpital Notre-Dame, 1560 Sherbrooke E, Montreal Québec, Canada.No affiliation info availableNo 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

22832115

Citation

Sylvester, Judith, et al. "Interleukin-1 Induction of Aggrecanase Gene Expression in Human Articular Chondrocytes Is Mediated By Mitogen-activated Protein Kinases." Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, vol. 30, no. 3, 2012, pp. 563-74.
Sylvester J, El Mabrouk M, Ahmad R, et al. Interleukin-1 induction of aggrecanase gene expression in human articular chondrocytes is mediated by mitogen-activated protein kinases. Cell Physiol Biochem. 2012;30(3):563-74.
Sylvester, J., El Mabrouk, M., Ahmad, R., Chaudry, A., & Zafarullah, M. (2012). Interleukin-1 induction of aggrecanase gene expression in human articular chondrocytes is mediated by mitogen-activated protein kinases. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 30(3), 563-74. https://doi.org/10.1159/000341438
Sylvester J, et al. Interleukin-1 Induction of Aggrecanase Gene Expression in Human Articular Chondrocytes Is Mediated By Mitogen-activated Protein Kinases. Cell Physiol Biochem. 2012;30(3):563-74. PubMed PMID: 22832115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interleukin-1 induction of aggrecanase gene expression in human articular chondrocytes is mediated by mitogen-activated protein kinases. AU - Sylvester,Judith, AU - El Mabrouk,Mohammed, AU - Ahmad,Rasheed, AU - Chaudry,Ataf, AU - Zafarullah,Muhammad, Y1 - 2012/07/23/ PY - 2012/7/27/entrez PY - 2012/7/27/pubmed PY - 2012/12/14/medline SP - 563 EP - 74 JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JO - Cell Physiol Biochem VL - 30 IS - 3 N2 - BACKGROUND/AIMS: We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And Metalloproteinase with ThromboSpondin motifs) in human articular chondrocytes, a model mimicking human arthritis. METHODS: Chondrocytes were pretreated with various pharmacological inhibitors and then stimulated with IL-1β for 24 h. ADAMTS-4 expression or activity was studied by RT-PCR or ELISA and other proteins measured by Western blotting. RESULTS: MAP kinase kinase-specific inhibitor, U0126 inhibited IL-1-induced phosphorylation of ERK1/2 and down-regulated ADAMTS-4 expression and activity. Protein 38 inhibitor, SB203580 down-regulated the phosphorylation of p38 and its target, activating transcription factor-2 (ATF-2), ADAMTS-4 mRNA and activity. C-Jun N-terminal kinase (JNK) inhibitor, SP600125 diminished IL-1-stimulated JNK phosphorylation, ADAMTS-4 mRNA expression and enzyme activity. A c-fos/lipoxygenase pathway inhibitor and antioxidant, nordihydroguaiaretic acid (NDGA) significantly suppressed ADAMTS-4 mRNA induction and activity. Activating protein (AP-1) and nuclear factor kappa B (NF-ĸB) transcription factor inhibitors, curcumin and pyrrolidine dithiocarbamate (PDTC) partially inhibited ADAMTS-4 induction and activity. CONCLUSION: These results suggest partial involvement of ERK-, p38-and JNK-MAPKs as well as AP-1, ATF-2 and NF-ĸB transcription factors in IL-1-induced ADAMTS-4 in chondrocytes. Inhibition of these targets by the specific pharmacological agents could be useful for reducing aggrecanase-driven cartilage resorption in arthritis. SN - 1421-9778 UR - https://www.unboundmedicine.com/medline/citation/22832115/Interleukin_1_induction_of_aggrecanase_gene_expression_in_human_articular_chondrocytes_is_mediated_by_mitogen_activated_protein_kinases_ L2 - https://www.karger.com?DOI=10.1159/000341438 DB - PRIME DP - Unbound Medicine ER -