Bone marrow monocytes (BMMs) are hematopoietic lineage cells that can differentiate into multinucleated bone-resorbing osteoclasts, while bone marrow stromal cells (BMSCs) of the mesenchymal lineage can differentiate into bone-forming osteoblasts.

Bone homeostasis is dependent on the coordinated efforts of both hematopoietic and mesenchymal lineage cells. The skeleton is a dynamic organ that continuously remodels through the coupled processes of bone resorption and bone formation ( 1). Our studies provide a potential rationale for co-administration of PTH1-34 and miR-29-3p inhibitors, to boost bone formation in severely affected osteoporosis patients, particularly in the cortical compartment. Overall, the global miR-29-3p tough decoy model represents a modest loss-of-function, which could be a relevant tool for assessing the possible impact of systemically administered miR-29-3p inhibitors. These findings highlight differences in the mechanisms controlling basal level bone formation and bone formation induced by intermittent PTH. In contrast, when mice were treated with intermittent parathyroid hormone (PTH1-34), inhibition of miR-29-3p augmented the effect of PTH on cortical bone anabolism, increased bone formation rate and osteoblast surface, and increased levels of Ctnnb1/βcatenin mRNA, which is a miR-29 target. These data support previous in vitro studies suggesting that miR-29-3p is a positive regulator of osteoblast differentiation. While the miR-29-3p decoy did not impact osteoclast number or function, the tough decoy decreased bone formation in growing mice, which led to decreased trabecular bone volume in mature animals. Using mice globally expressing a miR-29-3p tough decoy, we demonstrated a modest 30–60% decrease all three miR-29-3p isoforms: miR-29a, miR-29b, and miR-29c. MiRNAs play a vital role in post-transcriptional regulation of gene expression in osteoblasts and osteoclasts, and the miR-29 family is expressed in both lineages.

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