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Differential effects of p38MAP kinase inhibitors on the expression of inflammation‐associated genes in primary, interleukin‐1β‐stimulated human chondrocytes
Author(s) -
Joos H,
Albrecht W,
Laufer S,
Brenner RE
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00760.x
Subject(s) - chondrocyte , gene expression , microarray analysis techniques , microarray , cartilage , matrix metalloproteinase , microbiology and biotechnology , chemistry , pharmacology , cancer research , gene , in vitro , biology , biochemistry , anatomy
Background and purpose: A main challenge in the therapy of osteoarthritis (OA) is the development of drugs that will modify the disease. Reliable test systems are necessary to enable an efficient screening of therapeutic substances. We therefore established a chondrocyte‐based in vitro cell culture model in order to characterize different p38MAPK inhibitors. Experimental approach: Interleukin‐1β (IL‐1β)‐stimulated human OA chondrocytes were treated with the p38MAPK inhibitors Birb 796, pamapimod, SB203580 and the new substance CBS‐3868. Birb 796‐ and SB203580‐treated cells were analysed in a genome‐wide microarray analysis. The efficacy of all inhibitors was characterized by quantitative gene expression analysis and the quantification of PGE 2 and NO release. Key results: Microarray analysis revealed inhibitor‐specific differences in gene expression. Whereas SB203580 had a broad effect on chondrocytes, Birb 796 counteracted the IL‐1β effect more specifically. All p38MAPK inhibitors significantly inhibited the IL‐1β‐induced gene expression of COX‐2, mPGES1, iNOS, matrix metalloproteinase 13 (MMP13) and TNFRSF11B, as well as PGE 2 release. Birb 796 and CBS‐3868 showed a higher efficacy than SB203580 and pamapimod at inhibiting the expression of COX‐2 and MMP13 genes, as well as PGE 2 release. In the case of mPGES1 and TNFRSF11B gene expression, CBS‐3868 exceeded the efficacy of Birb 796. Conclusions and implications: Our test system could differentially characterize inhibitors of the same primary pharmaceutical target. It reflects processes relevant in OA and is based on chondrocytes that are mainly responsible for cartilage degradation. It therefore represents a valuable tool for drug screening in between functional in vitro testing and in vivo models.