Changes in primary cilia length and function modulate the pathogenesis of osteoarthritis in response to lithium

Principal investigator: Martin KNIGHT
Co-investigator(s): C.A. Poole
Funding source(s): AO Foundation
 Start: 01-10-2012  /  End: 30-09-2014
 Amount: £45,323
Directly incurred staff: Clare Thompson

Lithium elongates chondrocyte primary cilia - confocal image showing cilia labelled in red and nuclei labelled blue.Osteoarthritis has recently been shown to involve aberrant up-regulation of hedgehog signalling leading to increased expression of ADAMTS5 resulting in degradation of the articular cartilage. Hedgehog signalling requires the presence of a primary cilium, a specialised cytoskeletal organelle that projects out from the cell into the extracellular microenvironment. The length of the primary cilium is regulated by a process of interflagellar transport (IFT) which modulates the function of the cilium. The widely used psychiatric drug, lithium, is known to cause cilia elongation in a wide variety of cell types although the functional consequences are unclear. The proposed study will therefore test the hypothesis that lithium treatment influence chondrocyte primary cilia structure and associated hedgehog signalling leading to alterations in ADAMTS5 expression and cartilage degradation. Studies will examine the composition and structure of articular cartilage from the knee joints of rats given a lithium enriched diet at clinically relevant concentrations. We will use confocal microscopy to examine changes in primary cilia structure and length both ex vivo within the rat articular cartilage and using isolated chondrocytes cultured in monolayer. This will allow us to determine the precise dose response characteristics and the mechanism responsible for cilia elongation in chondrocytes. Quantitative PCR will be used to measure lithium induced changes in hedgehog signalling and ADAMTS5 expression and to identify whether these are triggered by changes in cilia structure. Finally we will utilise a cartilage explant model to investigate whether lithium causes cartilage degradation through changes in cilia structure. These studies will therefore enable further understanding of the role of the primary cilium in osteoarthritis and the specific effects of lithium on articular cartilage. Such studies may lead to the development of novel strategies for the treatment of osteoarthritis through manipulation of primary cilia structure and function.