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Abstract
Osteoporosts is a disease characterised by low bone mass and microarchitectural deterioration. of bone tissue leading to enhanced fragility and a consequent increase in fracture risk. In western society, the lifetime risk of a fragility fracture in a 50 year old Caucasian woman is 45% and in a man is 13%. A major question in osteoporosis research is why estrogen withdrawal at the menopause is associated with a decreased effectiveness of the mechanically adaptive response which matches bones' strength to their load-bearing. In both men and women the severity of bone loss is related to levels of bio-available estrogen. The mechanism underlying this association is not known since estrogen levels do not directly control bone mass. In contrast, mechanical loading substantially influences bone mass. Previous work from this laboratory has demonstrated that bone cells' early response to loading involves the estrogen receptor (ER) alpha. Recently, Wnt/b-catenin signalling has also been implicated in the regulation of bone mass through its involvement in bone cells' response to their mechanical environment. The aim of the study in this thesis was to determine whether the Wnt/b-catenin pathway was involved in bone cells' early responses to strain and if so whether the mechanisms of this response also involved the ER. Western blot and immunocytochemical analysis showed that in cells of the ROS 17/2.8 osteoblastic cell line a short period dynamic strain in vitro or lithium chloride (LlCl) treatment, an inhibitor of glycogen synthase kinase-Jf (GSK-3(3)), increased the expression of activated catenin and stimulated nuclear accumulation within 3 hours. Strain and LiCl also induced a significant increase in TCF/LEF mediated transcriptional activity. Estrogen treatment had no influence on the level or distribution of activated b-catenin at the time points studies, or any effect on TCF/LEF mediated activation.
