ECTS2013 Oral Communications Osteoblasts and osteocytes (6 abstracts)
Glucocorticoids (GC) are effective drugs in the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited by negative effects on bone mass and strength, resulting in increased osteoporotic fractures. Conditional knockout mice demonstrated that the GR in osteoblasts is essential for GC-dependent bone loss. Recent studies show that GC profoundly inhibit Wnt signaling by stimulating the expression of Wnt antagonists such as dickkopf-1 (Dkk-1). Here, we assessed the regulation of sclerostin (Sost), another Wnt inhibitor, by GC. Sost mRNA expression was down-regulated by 75% by 1 μM dexamethasone (DEX) in human bone marrow stromal cells (BMSC). Analysis of protein expression using ELISA confirmed these results showing a reduction of 13%. Furthermore, this reduction was time- and dose-dependent reaching a maximum suppression after 48 h at a concentration of 10 μM. Interestingly we detected a significant decrease in Sost mRNA expression after knock-down of the GR in BMSC using siRNA. This was validated ex vivo using osteoblasts isolated from GR knock-out mice which completely lacked Sost expression. In contrast, osteoblasts from GRdim mice expressed normal levels of Sost. However, compared to wild-type osteoblasts, in which Sost mRNA levels were decreased by 49% after DEX exposure, Sost was unchanged in osteoblasts from GRdim mice, indicating that GR dimerization is a critical mechanism for Sost regulation. Given that we previously demonstrated that GRdim mice lose bone in response to GC our data strongly suggest that regulation of Sost by GC is not essential for regulation bone mass by GC. In summary, we show that pharmacological concentrations of GC suppress Sost expression in a GR dimerization-dependent manner. Additionally, basic GR signaling seems to be required for Sost expression.
18 May 2013 - 22 May 2013