Inhibition of miR-29-3p isoforms via tough decoy suppresses osteoblast function in homeostasis but promotes intermittent parathyroid hormone-induced bone anabolism

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. 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,...

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Bibliographic Details
Published in:Bone (New York, N.Y.) N.Y.), 2021-02, Vol.143, p.115779-115779, Article 115779
Main Authors: Hrdlicka, Henry C., Pereira, Renata C., Shin, Bongjin, Yee, Siu-Pok, Deymier, Alix C., Lee, Sun-Kyeong, Delany, Anne M.
Format: Article
Language:English
Subjects:
Animals
Bone formation
Cell Differentiation
Homeostasis
Humans
Mice
MicroRNAs - genetics
miRNA-29
Osteoblast
Osteoblasts
Osteoclast
Osteogenesis
Parathyroid Hormone - pharmacology
Protein Isoforms
PTH
Tough decoy
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Summary: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. 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. 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. These data support previous in vitro studies suggesting that miR-29-3p is a positive regulator of osteoblast differentiation. 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 findings highlight differences in the mechanisms controlling basal level bone formation and bone formation induced by intermittent PTH. 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. 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. •The miR-29 family promotes osteoblast and osteoclast differentiation in vitro.•Mice globally expressing a miR-29-3p tough decoy have decreased trabecular bone volume.•In bone homeostasis, the miR-29-3p decoy suppresses bone formation.•In contrast, the miR-29-3p decoy augmented intermittent PTH mediated bone anabolism.•miR-29-3p plays a differential role in basal vs. PTH-mediated bone formation.
ISSN:8756-3282
1873-2763
DOI:10.1016/j.bone.2020.115779