| Summary: | <p>More than 50% of the UK population over 75 suffers from the degenerative cartilage disease osteoarthritis, but the mechanisms of pathogenesis remain elusive. While it is appreciated that joint mechanics are hugely influential to osteoarthritis and fundamental for cartilage development and homeostasis, the chondrocyte/cartilage ‘mechanostat’ is unknown. Chondrocytes assemble a primary cilium, a microtubule-based organelle reliant on intraflagellar transport (IFT). Mutations to ciliary genes alter the chondrocyte’s anabolic matrix response to compression in vitro. Perturbations to IFT in vivo alter embryonic and early post-natal skeletal development, but little is known of its cartilaginous influence in adulthood. The main aim of this thesis was to explore whether the core ciliary gene IFT88, and therefore likely the primary cilium itself, maintains influence beyond development in the contexts of adolescent and adult cartilage. A sub-aim preliminarily explored a role of IFT88 in cartilage matrix catabolism in vitro.</p>
<p>Experiments in vitro identified putative, novel regulation of aggrecaneolysis by IFT88, through control of the endocytic clearance of proteases. Establishment and validation of a cartilage-specific, inducible knockout mouse model (cKO) enabled the deletion of IFT88. Deletion during adolescence, resulted in longer growth plates, with large bilateral cartilaginous holes where the normal ossification programme associated with growth plate closure was inhibited. Thinner articular cartilage in cKO mice was exhibited throughout adolescence and adulthood and its progressive calcification was inhibited. The effects on cartilage thickness were most pronounced in plateaus that experience the highest compressive loads. Following deletion at skeletal maturity, some joints exhibited total loss of cartilage, associated with features of osteoarthritis 28- weeks later. Experimental osteoarthritis, instigated by destabilisation of the joint, was exacerbated in cKO animals.</p>
<p>These studies demonstrate that IFT88, and by extension the primary cilium, has a critical role in cartilaginous tissues, sustained throughout adolescence into adulthood. The results in this thesis suggest that in the growth plate and articular cartilage, IFT88 could be an integrator and dampener of extrinsic, physiological, mechanical cues and intrinsic ciliary signalling pathways such as hedgehog signalling, and thus critical to the maturation, homeostasis and health of the post-natal joint.</p>
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