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Title: The regulation of osteoprotegerin production by effectors of bone turnover
Author: Smith, Helen Louise
ISNI:       0000 0004 2742 7098
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2006
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Osteoprotegerin (OPG) is a protein produced by many cell types that has the remarkable property of inhibiting bone loss. It does this by binding to the key bone resorptive cytokine, receptor activator of NF-kB ligand (RANKL). This cytokine is produced mainly by osteoblastic cells and is instrumental in osteoclast differentiation. If the ratio of RANKL:OPG increases, bone resorption increases and results in bone loss in diseases such osteoporosis, rheumatoid arthritis and hypercalcaemia of malignancy. Hence, if drugs can be found that increase OPG, this will decrease the activity of osteoclasts and therefore bone resorption. Statins are cholesterol lowering drugs that have recently been shown to increase bone formation in rodents. It was hypothesised from this finding that this could be due to an increase in OPG production. If these commonly prescribed drugs could be used to prevent bone loss or to increase bone formation then this may prove a useful means of reducing fracture risk in patients. Treating Saos-2 osteoblast-like cells in vitro with mevastatin increased OPG production and secretion. However, it also increased apoptosis as identified by an increase in caspase-3 activity, nuclear pyknosis and decreased cell number. Statins caused many cells to lose adherence to the culture vessel, this was accompanied by a loss of F-actin stress fibres. Results show that statins act on Saos-2 cells through the mevalonate pathway. A failure of geranylgeranylation of Rho and/or farnesylation of Ras proteins leads to an increase in PI-3K activation then AKT activation leading to several different signalling pathways such as MAPK's and NF-kB. NF-kB and p38MAPK inhibitors prevented the statin stimulation of OPG but not the decrease in cell number, suggesting that statins regulate OPG secretion via PI-3K, p38MAPK and NF-kB. Caspase activation was prevented by a caspase-9 inhibitor and blebbistatin, an inhibitor of myosin-II and F-actin formation. However, these two inhibitors did not prevent cell death. This suggests caspase-3 activation is via F-actin rearrangement and caspase-9 activation, and that statin induced apoptosis can occur in a caspaseindependent manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available