Bone Abstracts

: Glucocorticoid-induced osteoporosis (GIO) is the most frequent secondary osteoporosis in patients undergoing steroid therapy.

Recently we demonstrated that the inhibition of bone formation in GIO is occurring in part via the suppression of autocrine cytokines by the glucocorticoid receptor (GR) monomer in osteoblasts (Cell Metab 11, 517–531). Since emerging evidences indicate that microRNAs (miRNAs) play a critical role in the differentiation of osteoblasts, we evaluated the impact of miRNAs in GIO by conditional ablation of the miRNA-processing enzyme Dicer in osteoblasts.

Runx2-Cre transgenic mice were crossed with Dicer^flox mice, and the resulting Dicer^Runx2Cre mice were growth retarded, accompanied with impaired bone formation and low bone density. qRT-PCR for representative miRNAs showed severe reduction of miRNA levels in femurs of Dicer^Runx2Cre mice. Similarly, calvarial osteoblasts with a conditional ablation of Dicer upon 4-hydroxytamoxifen treatment derived from mice expressing a Cre-Estrogen ligand binding domain (CreERT2) fusion protein (Dicer^{gtRosa26CreERT2}) displayed suppressed osteoblast differentiation. Importantly, ablation of dicer in primary osteoblasts did not affect dexamethasone-inhibited proliferation and differentiation in vitro. Accordingly Dicer^Runx2Cre mice treated with prednisolone for 2 weeks exhibited a strong inhibition of bone formation as WT mice.

Taken together, despite a strong impact on skeletal development, the conditional ablation of Dicer-dependent miRNAs in osteoblasts does not impair glucocorticoid-suppressed osteoblast differentiation and inhibition of bone formation. Our data suggest that miRNAs do not play a major role in GIO. Rather regulation of protein encoding genes or other Dicer-independently processed RNA species seem to mediate these deleterious glucocorticoid-effects.