The role of canonical and non-canonical WNT signalling pathways in load induced cartilage degradation.

Doctoral thesis English OPEN
Alsabah, Ayesha
  • Subject: QR

WNT signalling is a major driving force in cartilage development, chondrocyte differentiation, and homeostasis. Due to its major role in cartilage homeostasis, deregulation of this pathway was suggested to be involved in the pathophysiology of osteoarthritis, which causes cartilage degeneration. Studies have identified mutations in inhibitors of WNT signalling in OA tissue in addition to up-regulation of related WNT components. However, these studies have focused on the end stage of the disease and have not factored in mechanical loading which is one of the main regulators of cartilage homeostasis.\ud Results:\ud Canonical WNT signalling was activated in response to both tensile and compressive loading. Furthermore, WNT signalling was observed to be differentially regulated in bovine cartilage explants in response to physiological (2.5MPa, 1Hz, 15 minutes) and degradative (7MPa, 1Hz, 15 minutes) compressive loading in a zone dependent manner as indicated by β-catenin nuclear translocation. Based on periods post-cessation of load, physiological and degradative loads have induced differential matrix gene expression. In addition, both loading regimes have shown differential regulation of WNT signalling components displaying more WNT signalling activation in degradative loading regime. DKK-1 and NFATC, WNT signalling components which have shown to have a role in cartilage homeostasis, have been chosen for functional analysis studies. Treatment of recombinant DKK-1 in combination with degradative load have shown that DKK-1 primarily inhibited canonical WNT signalling pathway, whereas treatment with NFAT inhibitor induced inhibition of both WNT signalling pathways. In addition, both treatments were observed to inhibit some of the load-induced matrix gene changes. \ud Conclusions:\ud WNT signalling is mechano-regulated in articular cartilage. The differential expression of WNT signalling components in response to different mechanical load regimes indicates a role for these components in maintaining cartilage homeostasis.
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