We deciphered constituent parts of a signal transduction cascade that is initiated by
collagen II and results in the release of various pro-inflammatory
cytokines, including
interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released
collagen II fragments and pro-inflammatory
cytokines. We previously proposed
discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of
osteoarthritis, our study further investigates the hypothesis that
discoidin domain receptor 2 is a candidate receptor for
collagen II, and that
transcription factor NFkappaB,
lipid kinase PI3K, and the MAP
kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with
collagen II, and observed the outcome, specifically the changes in
interleukin-6 release. Knockdown was performed by
siRNA-mediated gene silencing in the case of
discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that
discoidin domain receptor 2 mediates the
collagen II-dependent release of
interleukin-6 in primary human chondrocytes and that MAP
kinases p38, JNK and ERK, as well as
transcription factor NFkappaB, are integral components of intracellular
collagen II signalling. Given the detrimental role of these molecules in
osteoarthritis, our findings provide new targets for more specific
therapeutics, which may have fewer side effects than those currently applied.