Involvement of the osteoblast in Paget's disease of bone

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dc.contributor.advisor Dorit Naot en
dc.contributor.advisor Jill Cornish en Matthews, Brya Grace en 2009-07-20T00:12:30Z en 2009-07-20T00:12:30Z en 2009 en
dc.identifier.citation Thesis (PhD--Medicine)--University of Auckland, 2009. en
dc.identifier.uri en
dc.description.abstract Paget’s disease is characterised by focal regions of accelerated bone turnover. The aetiology is unknown, but genetic and environmental factors have been implicated. Pagetic lesions contain increased numbers of osteoclasts with abnormal morphology, so an osteoclast defect has been considered central to the pathogenesis. However, given osteoblasts regulate osteoclast differentiation and activity; osteoblast abnormalities may be important in the disease. This study aimed to identify features of pagetic osteoblasts that could clarify their role in Paget’s disease. Gene expression in osteoblasts and bone marrow cultured from pagetic lesions of 23 patients was compared to cells from unaffected tissue using both microarrays and real time RT-PCR. The results indicated global changes in gene expression in pagetic osteoblasts. A number of genes that can stimulate osteoclastogenesis, including interleukins 6 and 1β, and monocyte chemotactic factor 1 were up-regulated, but the RANKL/OPG ratio tended to be decreased. Genes involved in osteoblast differentiation were down-regulated, including the transcription factors RUNX2, DLX5 and SATB2, the osteogenic factor BMP2, and the matrix proteins osteocalcin and bone sialoprotein. Markers of less mature osteoblastic cells, alkaline phosphatase and matrix gla protein were up-regulated. The intermediate filament, keratin 18, was very significantly up-regulated in pagetic cells. Over-expression of this protein in osteoblasts using an adenoviral vector produced some changes in gene expression, but did not produce an overtly pagetic phenotype. Over-expression of SQSTM1 mutants found in some patients with Paget’s disease also produced only minor changes in osteoblast phenotype. The RNA from the primary cell cultures was also used to investigate the presence of measles virus and somatic mutations in SQSTM1 in the disease, but neither were identified in any of the patients. These results suggest that there are important changes in pagetic osteoblasts that are maintained when the cells are removed from the affected bone microenvironment. These include enhanced production of factors to stimulate osteoclastogenesis, while osteoblast differentiation and activity may be impaired. We were unable to identify genetic or environmental factors that could trigger these changes. The pagetic osteoblast is distinct from control cells, and is likely to contribute to the development of Paget’s disease. en
dc.language.iso en en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA1908196 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri en
dc.rights.uri en
dc.subject Paget's disease en
dc.subject osteoblast en
dc.subject gene expression en
dc.title Involvement of the osteoblast in Paget's disease of bone en
dc.type Thesis en Medicine en The University of Auckland en Doctoral en PhD en
dc.subject.marsden Fields of Research::320000 Medical and Health Sciences en
dc.rights.holder Copyright: The author en
pubs.local.anzsrc 11 - Medical and Health Sciences en Faculty of Medical & Hlth Sci en

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