Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 19 OC3

SFEBES2009 Oral Communications Young Endocrinologist prize session (8 abstracts)

The role of gucocorticoid metabolism in osteosarcoma pathogenesis and treatment

P Patel 1 , R Hardy 1 , N Gittoes 1 , E Rabbitt 1 , L Kindblom 2 , P Stewart 1 & M Cooper 1

1School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, West Midlands, UK; 2Royal Orthopaedic NHS Trust, Department of Musculoskeletal Pathology, Queen Elizabeth Hospital, Birmingham, West Midlands, UK.

Osteosarcoma (OS) is an aggressive malignant tumour of osteoblasts occurring predominantly in children and young adults. Despite chemotherapy relapse is common and mortality remains ~50%. Non-transformed osteoblasts are highly sensitive to glucocorticoids which reduce proliferation and induce apoptosis. Previously, we observed that OS cells, but not normal osteoblasts, express 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme powerfully inactivates cortisol (active) to cortisone (inactive) and expression renders OS cells resistant to glucocorticoids. Some synthetic glucocorticoids (e.g. dehydrodexamethasone (DHD), inactive counterpart of dexamethasone (DEX)) have however been reported to be activated by 11β-HSD2. We therefore tested the hypothesis that such glucocorticoids might be selectively activated in osteosarcoma cells and thus form the basis for targeted anti-osteosarcoma therapy.

Expression of 11β-HSD2 in osteosarcoma tissue was examined in pathological specimens by immunohistochemistry and real-time PCR. Tritiated DHD was generated from DEX using placenta homogenates and the cofactor NAD. Enzyme kinetics of DHD to DEX conversion and its functional consequences were examined in cells stably expressing 11β-HSD2. Immunohistochemisty demonstrated high expression of 11β-HSD2 in OS tissue from biopsy specimens whereas expression was absent in normal bone. Tritiated DHD was successfully generated from tritiated DEX. Cells that lacked 11β-HSD2 were unable to activate DHD and were thus unresponsive. By contrast cells expressing 11β-HSD2 were able to generate active DEX from DHD (activity rate 1.2 pmol/h per million cells). The apparent Km and Vmax were 1463 nM and 57.98 pmol/h per million cells. Interestingly cells expressing 11β-HSD2 were also able to inactive DEX to DHD (activity rate 4.1 pmol/h per million cells). These studies indicate that 11β-HSD2 is expressed at high levels in OS tissue in vivo and that OS cells can selectively activate glucocorticoids. This indicates that targeting of cytotoxic medications to OS tissue via the expression of 11β-HSD2 has potential as a novel treatment for this disease.

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