Projects

Our current projects are:

• Preventing The Spread Of Malignant Tumours To Bone - details here
• Glucocorticoid-Induced Changes in Bone Metabolism - details here
• Regulation of osteoblast and adipocyte differentiation from common precursors - details here
• Study into the genetic determinants of bone loss and osteoporosis - details here
• Studies on Bone Metabolism and Calcium Homoestasis  - details here
• Studies into the influence of sex hormones and their longitudinal changes on different target tissues of androgen action - details here

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Breast cancer and prostate cancer have a particular preference to form cancer metastases in bone. Breast cancer in bone is associated with bone destruction that frequently results in significant pain and disability. Prostate cancer cells in bone induce high rates of bone formation and bone resorption, resulting in disorganisation of bone structure and severe pain. Tumour cells grow in bone and induce normal bone resorbing and bone forming cells of the bone marrow to destroy the surrounding hard bone. It is proposed that destruction of bone releases factors that help cancer cells grow faster, thus creating a vicious cycle that contributes to the serious consequences of bone metastases. We are also examining how physiologic bone remodelling may support the earlier stages of bone metastasis of extravasation and formation of micrometastases. We are studying mice with transplanted breast cancer cells to understand what makes the bone marrow a receptive site for breast cancer metastasis. We are manipulating bone remodelling rates in mice see how this impacts the ability of circulating cancer cells to target bone and to establish destructive tumours there. We have determined that anti-resorptive treatments inhibit tumour growth in bone indirectly through effects on osteoclasts, rather than directly through effects on tumour cells. We have discovered that increasing bone resorption through a low calcium diet enhances breast cancer metastasis to bone in a mouse model. This may have clinical implications as many elderly women at risk of breast cancer have secondary hyperparathyroidism and increased levels of bone resorption. The response of tumours to these changes in bone cell activity is being assessed at the cellular and molecular levels to identify genes that may be critical to the metastatic process.

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Osteoblasts and adipocytes develop from a common mesenchymal precursor. An inverse relationship between adipocyte and osteoblast differentiation has been suggested by the clinical observation that marrow adipocyte numbers increase while osteoblast numbers decrease during age-related bone loss or after treatment with glucocorticoids. In this study, we aim to identify the factors that control commitment at the branching pointing between osteoblast and adipocyte differentiation. Steroid hormones play an important role in regulating osteoblast and adipocyte differentiation. By using the transgenic mice model, we have found that glucocorticoids stimulate mature osteoblast cells produce the molecules to inhibit adipocyte differentiation and promote osteoblast differentiation. Further studies are planned to determine the gene expression profile in this system. With our collaborators, Prof. Franz Jacob and Dr Norbert Schuetze from the University of Wuerzburg, Germany, we have conducted microarray and proteomic studies into signalling between osteoblasts and osteoblast precursors. We will utilise transgenic mice with impaired osteoblast formation to identify specific autocrine and paracrine factors involved in the regulation of osteoblast differentiation.

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Osteoporosis is a common multifactorial disorder of reduced bone mass. Osteoporosis treatments are currently limited in terms of efficacy and drug classes available. Identification of new therapeutic targets is a high priority. Although multiple environmental factors are involved in the pathogenesis of osteoporosis, genes also play a major role as reflected by heritability of many components of bone strength. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at many loci. However, a few recent publications have reported a major gene pattern of BMD inheritance in several ethnic populations. Identification of major genes contributing to osteoporosis would be of value for assessment of risk in individual patients.

In collaboration with Drs Ian Blair and Marina Kennerson, and Professor Garth Nicholson, Neurobiology Laboratory, ANZAC Research Institute and Molecular Medicine Laboratory, Concord Hospital, we are currently studying a large family with an autosomal dominant inheritance pattern of low bone mineral density. We have obtained DNA samples and clinical data from this extensive family and are examining the results to determine the best approach for identification of candidate genes.

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All metabolic bone diseases are characterised by changes in bone formation and in bone re­sorption, the two major proces­ses that keep bone alive, healthy and strong. Measurement of spe­cific ‘bone markers’ in serum and urine determines the activity of these processes and the results of these simple tests can help the clini­cian assess the severity, and monitor the treatment of bone di­seases such as osteoporosis.

Although these “bone markers” have been developed only recently and are still being refined, they are already widely used amongst clinicians world­wide. Led by Markus Seibel, we are focussing on the development and experimental and/or clinical validation of novel or improved markers of bone turnover.

Present studies focus on the evaluation of bone turnover in the very elderly (with Professor Philip Sambrook, RNSH), the effect of androgens on male bone health (with Professor David Handelsman and Dr Peter Liu, ARI), the effect of growth hormones and androgens on bone metabolism in elite athletes (with Professor Ken Ho), the effect of anti-epileptic drugs and smoking on bone turnover (with Prof. John Wark, Melbourne), and other topics.

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