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Title: Role of endothelium in osteoclast formation from human peripheral blood precursors in health and disease
Author: McGowan, Neil W. A.
ISNI:       0000 0001 3624 4128
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2002
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Osteoclasts are large multinucleated cells responsible for the degradation of bone matrix. Osteoclast precursors (OCL-Ps) are of haematopoietic origin, being members of the mononuclear phagocyte system that circulate amongst the fraction of CD14+ cells in peripheral blood. OCL-Ps reach sites of osteoclast formation and remodelling via the vasculature and are therefore destined to encounter endothelium before migrating to the bone surface. The main aim of this study was to design a suitable model for the investigation of OCL-P-endothelial interactions. Adaptations of this culture system were also used to examine osteoclast formation in health and disease. Firstly, osteoclast formation from PBMCs was investigated using a soluble Receptor Activator of NF-kB Ligand (sRANKL)-based culture system. Osteoclasts could be consistently generated from the PBMCs of healthy volunteers. These cells were multinucleated, expressed TRAcP and VNR, formed F-Actin rings and were capable of forming extensive resorption lacunae on dentine slices. Osteoclast formation was most efficient in the presence of RANKL, MCSF, 1,25-VitD3, dexamethasone and PGE2, required 21 days of culture and was critically dependent on the presence of RANKL and MCSF. Cell selection studies revealed that the OCL-P resided solely within the CD14+ fraction and lymphocyte depletion had no significant effect on osteoclast formation. This culture system was subsequently utilised to examine and compare osteoclast formation in bone disease. No consistent differences in osteoclast formation or resorption were observed between patients with Paget's disease of bone (PDB) or osteoporosis compared to healthy volunteers. When osteoclast formation was compared between patients with Familial Expansile Osteolysis, a severe form of PDB and unaffected immediate relatives, no statistically significant differences were observed. However, osteoclast formation from patients with sclerotic bone disorder Camurati-Englemann disease (CED) was elevated 5-fold, and resorption 10-fold, when compared to both family-based and unrelated controls. CED is caused by mutations in the transforming growth factor-betal (TGF-1) gene, which leads to increased TGF-1 bioavailability.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available