ECTS Abstracts (2015) 1 OC1.1

Wnt16 promotes osteoblastogenesis and is negatively regulated by glucocorticoids in vitro and in vivo

Susanne Hildebrandt1, Sylvia Thiele1, Ulrike Baschant1, Juliane Salbach-Hirsch1, Jan Tuckermann2, Lorenz C Hofbauer1,3 & Martina Rauner1


1Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; 2Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany, 3Center for Regenerative Therapies Dresden, Dresden, Germany.


Glucocorticoids (GCs) are effective drugs to treat inflammatory diseases, but exert detrimental effects on bone when used over longer periods of time. One of the main mechanisms of GC-induced bone loss is the suppression of osteoblast activity. Osteoblast-derived Wnt16 has recently been shown to determine cortical bone mass by regulating osteoclast function. However, its role in osteoblastogenesis and its regulation by GCs remain unknown. Here, we assessed the role of Wnt16 during osteoblast differentiation and tested whether GCs regulate Wnt16 expression. Wnt16 was highly expressed in primary murine bone marrow stromal cells (BMSCs), promoted osteoblastogenesis and activated canonical Wnt signalling in MC3T3-E1 cells. GC treatment using dexamethasone (DEX) decreased Wnt16 mRNA expression levels by 50% ex vivo in BMSCs. Wnt16 suppression was dose-and time-dependent, reaching a maximum after 48 h at a concentration of 1 μM. Consistently, treatment of mice with GC-containing slow-release pellets for two weeks reduced vertebral bone mineral density by 13% and Wnt16 mRNA levels by 35% in bone tissue. The suppression of Wnt16 by GCs was strictly GC receptor (GR)-dependent. Co-treatment of BMSCs with DEX and the GR antagonist RU-486 completely abrogated the GC-mediated suppression of Wnt16. Likewise, DEX failed to suppress Wnt16 expression in BMSCs derived from GR knockout mice. Additionally, Wnt16 mRNA levels were unaltered after GC treatment in bone tissue of GRdim mice, which lack the ability of GR dimerisation and therefore binding of the GR to DNA, suggesting that GCs suppress Wnt16 via direct DNA-binding mechanisms. In line with this, DEX treatment reduced Wnt16 promoter activity in MC3T3-E1 cells. Thus, this study underlines the pro-osteogenic effect of Wnt16 and identifies Wnt16 as a novel GC target. As the suppression of Wnt16 could define a mechanism of reduced osteoblast activity, Wnt16 may represent a novel target for therapeutic intervention in GC-induced bone loss.

Disclosure: The authors declared no competing interests.

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