Enhanced bone resorption is a common pathology in destructive bone diseases. Many cytokines (e.g. IL-6 and TNF-α) and chemokines (e.g. CCL2, CCL3 and CCL5) elevated in patients exert pathological roles in leukocyte migration and inflammation, but their effect on direct bone destruction remained elusive. Published research into osteoclastogenesis was carried out in co-cultures, from which osteoclast differentiation, resorption and mediator secretion data was obtained. The main objective of this thesis was to establish a working methodology for the in vitro differentiation of CD14+ve mononuclear cells into osteoclasts and to decipher the direct effects of IL-6 and CCL3 on osteoclastogenesis and bone resorption. IL-6 trans-signalling exerted an effect in both basal and pathological osteoclastogenesis, whereas its inhibition via sgp130-Fc significantly reduced osteoclast formation and bone resorption in vitro. Although not examined in vivo, the translational use of sgp130-Fc as a therapeutic for destructive bone pathology was postulated from data showing a reduction in osteoclast differentiation and resorption after stimulation with HYPER-IL-6. Secondary to IL-6 trans-signalling, it was hypothesised that the neutralisation of CCL3 in vitro and in vivo would significantly reduce osteoclast differentiation and resorption. Osteoclast number significantly reduced in the presence of anti-CCL3, but TRAP+ve cell count was unaltered, suggesting an early role of CCL3 in osteoclast multi-nucleation/fusion. Additionally, in vivo data showed a protective effect of anti-CCL3 with significantly reduced bone erosive scores and osteoclast counts thereby presenting CCL3 as a novel biomarker of disease activity in destructive bone disease. In contrast, TNF-α, CCL2, and CCL5 were shown to have no role in direct osteoclast differentiation in our monocultures. In conclusion, for the first time this work documents novel and important roles of IL-6 trans-signalling and CCL3 in increased osteoclast differentiation and bone resorption. Our data highlights the importance of IL-6 trans-signalling and provides evidence for the use of CCL3 as a predictive biomarker in destructive bone diseases.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:709583 |
| Date | January 2016 |
| Creators | Jordan, Lauren |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/99566/ |
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