Student thesis: Doctoral ThesisDoctor of Philosophy


The rapid bone destruction of the acute Charcot foot is well documented. Osteoclasts are the principal cells responsible for bone resorption but their activation and function in Charcot osteoarthropathy remain unresolved.
I hypothesised that aberrantly activated osteoclasts play a key role in the pathological bone destruction of the acute Charcot foot. I studied the role of receptor activator of nuclear factor-kβ ligand (RANKL), as an osteoclastic activator in Charcot osteoarthropathy. I also assessed the role of the proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) on osteoclastic activity by using neutralising antibodies (anti-TNF-α and anti-IL-6).
I introduced for the first time in the field of Charcot osteoarthropathy a wellestablished osteoclast culture assay together with a novel method to quantitate resorption on bone discs, namely surface profilometry.
I demonstrated the usefulness of these methods as novel techniques to investigate osteoclastic activity in Charcot osteoarthropathy. My studies revealed that in the presence of macrophage-colony stimulating factor (M-CSF), a survival factor, and RANKL, osteoclastic precursors derived from patients with acute Charcot osteoarthropathy exhibited increased resorbing activity. This activity was attenuated by osteoprotegerin (OPG), a decoy receptor for RANKL, confirming the role of RANKL as an osteoclast activator. The addition of anti-TNF-α to M-CSF+RANKL-treated cultures led to a significant reduction in the area of resorption (at and below surface) of resorbed bone discs and reversed the aberrant erosion profile. The addition of anti-IL-6 to MCSF+ RANKL-treated cultures resulted only in reduction of the area of resorption at the surface.
My observations shed light on the pathogenesis of increased osteoclastic activity in acute Charcot osteoarthropathy and have pointed out several possible cellular targets that may be important for planning future therapies in this devastating condition.
Date of Award2015
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMichael Edmonds (Supervisor), Cathy Shanahan (Supervisor) & Alan McGregor (Supervisor)

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