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Title: Molecular mechanisms mediating the action of tri-triiodothyronine in human osteoblast like cells
Author: Parsons, Marie Patricia
ISNI:       0000 0001 3474 2895
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2007
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The mechanisms underlying the action~fT3 on osteoblastic cytokine production have been investigated. Western Blotting studies demonstrated the expression of . functional thyroid hormone receptor (TR) isoforms in primary cultures of osteoblasts (hOb) in human bone marrow stromal cells (hBMS) and in the transformed human osteosarcoma cell lines MG63 and SaOs-2. TRal, TRpl and TRp2 proteins were expressed in all cells although expression was greatest in MG63>hBMS>SaOs-2>hOb. Differences between isoforms were also apparent with TRal> TRp1>TRp2 in all cell types. Transfection studies using an IL6 promoter construct demonstrated constitutive transcription in MG63 cells unaffected by T3 treatment- a finding confirmed in hBMS. Similar studies using an IL8 promoter construct showed that T3 did significantly increase IL8 promoter activity. Studies with actinomycin D suggested that T3 was able to stabilise IL6 mRNA and the presence of two IL6 mRNA transcripts (492bp, 570bp) was shown in MG63 and hBMS cells with production of the more stable 492bp transcript being increased by T3. Potential mechanisms of cytokine stabilisation were investigated and T3 was shown to activate the'p44/42 mitogen-activated protein kinase (MAPK) in MG63 cells by a protein kinase C (PKC)-dependent mechanism. These studies have shown for the first time that differential TR expression occurs in human bone. T3-mediated transcriptional effects on IL6 were minimal but were significant for IL8. A novel mechanism for T3 stabilisation ofIL6 mRNA was demonstrated involving differential usage ofpolyadenylation signals within the IL6 gene. Studies on MAPK signaling, whilst demonstrating clear cut effects of T3 on this pathway, require further investigations to link MAPK activation with IL6 mRNA stabilisation in osteoblasts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available