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Title: The effects of estrogen and SERMs on bone cell viability
Author: Huber, Christina
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Although the beneficial role of other anti-resorptive agents such as the Selective Estrogen Receptor Modulators (SERMs) in preventing bone loss in postmenopausal osteoporosis are well established, the effects of SERMs on the maintenance of the osteocytic population in vivo are less clear. Work in this thesis has investigated whether the SERM LY 117018, which is a Raloxifene analogue, can mimic the osteocyte-sparing effect of 17β-estradiol in a rat model of ovariectomy. Abrupt estrogen withdrawal was shown to increase osteocyte apoptosis in rat bone, while the ovariectomy-induced stimulation of osteocyte apoptosis in rats was shown to be reversed following administration of the LY 117018 SERM in a similar way to the known effect of 17β-estradiol replacement. These data point to the potential benefits of SERMs on bone viability in estrogen-depleted rats. However, the molecular mechanism by which 17β-estradiol and the LY 117018 SERM maintain the osteocytic population has not been well characterised. In vitro studies in this thesis indicated that 17β-estradiol; raloxifene and LY 117018 suppressed the pro-apoptotic stimuli induced in response to H2O2 in osteocyte cultures possibly by exerting direct anti-oxidant properties related to their chemical structure. These data introduced a novel mechanism of action for 17β-estradiol, raloxifene and LY117018 as antioxidants, in the protection of the osteocytic population increasing the knowledge available on their activity in bone. In addition, these data suggested that the effects of SERMs on preventing osteocyte apoptosis will in future help to determine their effectiveness and interest for the clinical development of estrogen replacement compounds with activities consistent with the maintenance of both bone mass and bone quality. Finally, the effects of 17β-estradiol on the viability of osteocytes were investigated in human cancellous bone ex vivo in the presence or absence of mechanical loading. Results pointed to important anabolic effects induced by either 17b-estradiol or mechanical stimulation and have suggested that the osteogenic response of loading was not enhanced by the presence of 17β-estradiol in this patient. In this study, identification of anti-apoptotic effects of SERMs on osteocytes in vivo and in vitro highlighted an important bioactivity that may explain part of the action of SERMs in vivo. Further characterisation of the anti-apoptotic effects of 17β-estradiol and SERMs in vitro indicated direct antioxidant capabilities pointing to the possibility the SERMs mimic not only the bone sparing activity of 17β-estradiol but its anti-oxidant nature as well.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available