Expression of 11β-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments

Abstract

Osteosarcoma (OS) is a primary malignant tumour of bone occurring predominantly in children and young adults. Despite chemotherapy, relapse is common and mortality remains high. Nontransformed osteoblasts are highly sensitive to glucocorticoids, which reduce proliferation and induce apoptosis. Previously, we observed that OS cells, but not normal osteoblasts, express 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). This enzyme inactivates cortisol (active) to cortisone (inactive) and expression of 11b-HSD2 renders OS cells resistant to glucocorticoids. By contrast, the related enzyme 11b-HSD1 converts cortisone to cortisol and reduces OS cell proliferation in vitro. Some synthetic glucocorticoids (e.g. dehydrodexamethasone (DHD), inactive counterpart of dexamethasone (DEX)) have been reported to be activated by 11b-HSD2. We therefore investigated expression and enzymatic activity of 11b-HSD isozymes in human OS tissue, determined whether 11b-HSD expression has prognostic value in the response to therapy, and evaluated the potential use of synthetic glucocorticoids to selectively target OS cells. OS samples expressed both 11b-HSD1 and 11b-HSD2. 11b-HSD1 expression in pretreatment biopsy specimens positively correlated with primary tumour size. Expression and activity of 11b-HSD1 in post-treatment biopsies were unrelated to the degree of tumour necrosis following chemotherapy. However, high 11b-HSD2 expression in post-treatment biopsies correlated with a poor response to therapy. OS cells that expressed 11b-HSD2 inactivated endogenous glucocorticoids; but these cells were also able to generate DEX from DHD. These results suggest that OS treatment response is related to 11b-HSD2 enzyme expression. Furthermore, OS cells expressing this enzyme could be targeted by treatment with synthetic glucocorticoids that are selectively reactivated by the enzyme.

Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway

“…The results were consistent with the experimental results of HC combined with thiram, suggesting that inhibition of 11HSD2 is important for HC curing of osteosarcoma. These results are consistent with reports that 11HSD2 is highly expressed in osteosarcoma cells and human osteosarcoma tissues [ 46 ] and that the activity of 11HSD1 could not be detected in human osteosarcoma tissues, but only 11HSD2 and the expression of 11HSD2 were significantly correlated with poor prognosis of chemotherapy [ 47 ].…”

11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

“…The expression and activity of 11β-HSD1 in human bone along with its potential role in bone biology are extensively described in the literature 4,[26][27][28][29] . Short-term administration of oral GCs has a potent impact on bone turnover markers in healthy male individuals, decreasing osteocalcin and P1NP and increasing CTX 16 .…”

Blocking the Mineralocorticoid Receptor Improves Effectiveness of Steroid Treatment for Low Back Pain in Rats

“…Hence either local aldosterone or locally elevated corticosterone could plausibly act as endogenous MR activators in locally inflamed DRG. These enzymes present another confounding factor for predicting in vivo effects of clinically used steroids, only some of which metabolized by 11β-hydroxysteroid dehydrogenases 43,44 .…”