Dicer1 ablation in osterix positive bone forming cells affects cortical bone homeostasis

Abstract

The RNAse III enzyme Dicer plays a major role in the processing of microRNAs from large pre-miRNAs. Dicer1 processed microRNAs are known to play a comprehensive role in osteoblast differentiation, bone remodeling and skeletal disorders. Targeted deletion of Dicer1 in osteo-progenitor cells is deleterious to fetal survival whereas targeted deletion in mature osteoblasts leads to an increase in bone mass. To address the role of Dicer1 in post-natal skeletal homeostasis, we generated a pre-osteoblast specific Dicer1 knockout model employing Tamoxifen controllable Cre allele, enabling us, via tamoxifen administration, to time-controllably ablate Dicer1 gene expression in osterix expressing bone forming cells in post-natal mice. Inactivation of Dicer1 in osterix positive bone forming cells led to striking dysregulation of cortical bone formation in pre-pubertal as well as adult mice. Cortical bone thickness was found to be significantly decreased in the Cre+ femora of both young and adult mice. Further, biomechanical testing experiments showed increased ductility, reduced stiffness and altered load at upper yield among the Cre+ tibiae. Our results suggest that Dicer1 processed microRNAs might play an important role in the regulation of post-natal cortical bone formation.