Tobias, Jonathan Harold; (1991) The effects of steroid hormones on osteoclast function. Doctoral thesis (M.D), University of London, St. George's Hospital Medical School.

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Abstract

Although steroids are known to exert important actions on the skeleton, little is known of their effects on osteoclasts. This thesis therefore investigates the effects of hydrocortisone (HC), dexamethasone (DEX), 1715-estradiol (E2), tamoxifen (TAM), 5a-dihydotestosterone (DHT) and progesterone on the principle function of osteoclasts: bone resorption. DHT and progesterone had little influence over bone resorption by osteoclasts disaggregated from neonatal rat long bones, as assessed by scanning electron microscopy. By contrast, HC and DEX were found to reduce bone resorption, due to an inhibitory action on osteoclast survival. Since the latter was antagonised by progesterone, a receptor-mediated mechanism was thought to be responsible. The effects of E2 were more complex. Higher concentrations caused delayed stimulation of bone resorption by isolated cultures of osteoclasts, whereas lower concentrations of E2 led to moderate inhibition in mixed osteoblast- osteoclast co-cultures obtained by extended sedimentation of the rat long bone suspension, and by the addition of calvarial or osteosarcoma (UMR and HOS) cells. In the presence of TAM, which was itself without effect, neither stimulatory nor inhibitory actions of E2 were evident, again suggesting a receptor-dependent process. However, E2 did not appear to influence osteoclast differentiation in mouse bone marrow cultures, as defined by bone resorption and the development of cell surface receptors for calcitonin. Following an in vivo study, no evidence for a stimulatory effect of high concentrations of E2 on bone resorption in adult female rats was found, as assessed by histomorphometric and biochemical parameters, although an unexpected increase in bone formation was observed. Therefore, while direct actions of steroid hormones on osteoclastic bone resorption may be involved in adapting skeletal regulation to the needs of reproduction and stress, the skeletal response elicited by these hormones in the intact animal may be substantially modified, presumably due to the co-existence of significant indirect effects.

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