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Title: Biological significance of osteocyte apoptosis
Author: Kogianni, Georgia
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Work in this thesis has focused on identifying a biological role for the incidence of osteocyte apoptosis, the identity of osteocyte-derived resorption targeting signals and addresses the design of methods of blockade of the excess apoptosis observed during the use of glucocorticoids. An early event in the bone resorption process is the clearance of osteoblasts; hence I have studied the effects of osteocyte apoptotic bodies on osteoblastic cells. Apoptotic bodies derived from different cell types were also used to determine behavioural responses in osteoblast and other potential target cells. Osteoblasts were shown to undergo apoptosis upon contact with osteocyte apoptotic bodies, while apoptotic products derived from different cell types, did not induce osteoblast death. Furthermore, target cells other than osteoblasts, did not undergo apoptosis in the presence of osteocyte or other cell type apoptotic products. These data indicated a specific role for osteocyte apoptosis in the bone microenvironment that might be directing the behaviour of osteoblasts in the bone remodelling process.  In addition, the demonstration of phenotypic specificity in the apoptotic body-derived signals points to a further level of physiological “meaning” to apoptosis. The physical interaction of apoptotic osteocytes with osteoblasts and the resultant osteoblast death were dependent t on membrane changes in the apoptotic body and appeared to involve the phagocytic receptors CD14 and scavenger receptor A as evidenced by using gene knockout animal models. Having identified an important potential role for apoptotic osteocytes in targeting osteoblast removal at sites of remodelling, mechanisms that could interfere with the induction of osteocyte apoptosis in response to Dexamethasone were investigated. Dexamethasone-induced apoptosis was associated with activation of the Fas death receptor and ERK1/2 pathways. Bisphosphonates suppressed the pro-apoptotic stimuli, independently of their detailed structure and their in vivo anti-resorptive potency. These data suggested that bisphosphonates could provide therapeutic approaches against excess osteocytic death observed in glucocorticoids-induced osteoporosis in order to maintain a balance between osteocyte viability and death, which might ultimately lead to stabilised bone turnover activity and better bone quality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available