Signal transducers and activators of transcription (STAT) factors are cytoplasmic
proteins that can be activated by
Janus kinases (JAK) and that modulate gene expression in response to
cytokine receptor stimulation. STAT
proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that
interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3
proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the
DNA binding of the STAT
proteins. The
mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2
proteins. In these conditions, the expression of cartilage-specific matrix genes,
type II collagen,
aggrecan core, and link
proteins was found to be markedly down-regulated. This negative effect was abolished by addition of
parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP
kinases with
PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by
IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These
IL-6 effects might contribute to the phenotype loss of chondrocytes in
joint diseases and the alteration of articular cartilage associated with this pathology.