Investigating the structure-function relationships of long bone: An approach using growth hormone mouse models.

Abstract

Treating bone fragility diseases in humans has always been a challenging task with which clinicians and researchers are constantly faced. Growth hormone (GH) is one of many agents that are used to treat bone fragility diseases. However, its effects on bone have never been fully investigated. This dissertation used a systematic and hierarchical approach, combining both biological and mechanical principles, to investigate the effects of GH on long bone's structure-function relationships, hoping to gain more insights into the use of growth hormone in treating bone fragility diseases. The results showed that over-stimulation of GH, either endogenous or exogenous, could be detrimental to both bone quantity and quality. When compared to the littermate controls, GH transgenic femur specimens (from hGH and Mt-GHRH transgenic mice) had significantly higher fractions of woven bone, cartilage islands and porosity, as well as lower ash content, which all contributed to the observed lower cortical bone tissue mechanical properties in the transgenic specimens. Long-term over-stimulation of GH also induced increases in endocortical and intracortical bone resorption, resulting in thinner femoral cortices and worsening of whole bone mechanical properties. Exogenously giving high doses (8.0 mg/kg BW) of ovine growth hormone into normal mice induced increased bone formation, but the increase in bone quantity occurred at the expense of bone quality, as seen in the two transgenic mouse models. In summary, long-term over-stimulation of GH in mice had induced increased bone formation, but the resultant bone was of poor quality. With continual GH over-stimulation, whole bone mechanical properties deteriorated further due to an increased resorption activity. Given the popular use of GH in clinical settings and in view of the results of this dissertation, more studies need to be done to fully understand the effects of GH on bone.