Primary cilia are poorly understood cytoskeletal organelles that projects into the extracellular milieu. The chondrocytes cilium acts as a centre for Hedgehog (Hh) signalling which has recently been shown to be up-regulated in osteoarthritis where it drives cartilage degradation [31]. However the mechanisms leading to aberrant Hh signalling have not been identified. Preliminary data show that the inflammatory cytokine, IL-1β, which is up-regulated in osteoarthritis, triggers a significant increase in primary cilia length. We hypothesise that this cytokine-mediated ciliogenesis activates changes in cilia function, including Hh signalling. We will therefore identify the underlying mechanisms through which cytokines modulate cilia length, including the involvement of adenyly cyclise, calcium signalling and the actin remodelling. We will then determine the consequences for cilia-mediated Hh signalling, and downstream cartilage matrix synthesis and catabolism. Studies will utilise isolated primary chondrocytes and cartilage explants as well as transgenic chondrocytes that lack primary cilia. We will ultimately determine whether manipulation of ciliogenesis can down-regulate cytokine-induced changes in primary cilia function and thus identify novel cilia-related therapeutic targets to attenuate cartilage degradation.

See: www.primarycilia.qmul.ac.uk