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Title: Role of thyroid hormone receptor alpha in susceptibility and progression of osteoarthritis
Author: Waung, Julian
ISNI:       0000 0004 7658 3820
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Osteoarthritis (OA) is a debilitating joint disease characterised by articular cartilage damage, chondrocyte hypertrophy and subchondral bone changes. Thyroid hormone (TH) regulates chondrocyte differentiation, endochondral ossification and bone maintenance, acting mainly through thyroid hormone receptor alpha (TRα). Genetic, pathological and experimental data have implicated a role for TH availability in OA pathogenesis. I hypothesised that inhibition of TH signalling will decrease susceptibility to OA and delay disease progression. Osteoarthritis was assessed in mice treated with dronedarone (a TRα antagonist), TRα knockouts (TRα0/0) or wild type controls 4, 8 and 16 weeks after joint destabilisation surgery (DMM). Overall, articular cartilage damage was not reduced in either mutant or dronedarone treated mice but the studies were underpowered. Subchondral bone mineral content (BMC) in sham operated knees was increased in mutants but reduced with dronedarone treatment. Destabilising surgery increased subchondral BMC and mass but changes were attenuated in mutant and dronedarone treated mice. Mutant mice lacking iodothyronine deiodinase type 2 (D2KO) that are unable to activate thyroid hormone locally were investigated for OA development with ageing. Mutants had no change in cartilage damage but had increased subchondral BMC. TRα was further investigated as an osteoporosis drug target. Significantly, dronedarone increased femoral cortical thickness and BMC but did not affect bone strength. These results suggest a regulatory role for TH in subchondral bone remodelling. The absence of chondroprotection suggest that any potential role of TH in osteoarthritis pathogenesis may be mediated via subchondral bone. Further adequately powered studies with dronedarone are needed to confirm cartilage and bone observations and should include mechanistic studies to explain subchondral bone changes. Further experiments using established models of osteoporosis and more sensitive measures of bone strength should be used to confirm TRα as a novel drug target for osteoporosis.
Supervisor: Williams, Graham ; Bassett, Duncan Sponsor: Arthritis Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral