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The microRNA-455 null mouse shows dysregulated bone turnover
Lingzi Niu1, Tracey E Swingler1, Caterina Suelzu2
1Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.
JBMR Plus
|February 18, 2025
Summary
MicroRNA-455 (miR-455) deficiency in mice leads to increased bone length and density in young animals. This bone phenotype is linked to altered osteoblast and osteoclast activity, with FGF18 identified as a key target.
Area of Science:
- Molecular Biology
- Genetics
- Bone Biology
Background:
- MicroRNAs (miRNAs) play crucial roles in regulating bone mass by influencing osteoblast differentiation and function.
- Previous studies have identified specific miRNAs affecting bone metabolism, but the role of miR-455 remained largely uncharacterized.
- Our prior work generated a miR-455 knockout mouse model, revealing age-dependent behavioral changes.
Purpose of the Study:
- To investigate the impact of miR-455 deficiency on bone development and structure.
- To identify the underlying molecular mechanisms, including specific gene targets, responsible for miR-455's effects on bone.
- To characterize the bone phenotype in miR-455 null mice across different age points.
Main Methods:
- Generation and phenotypic analysis of miR-455 null mice using CRISPR-Cas9 technology.
- In vivo assessment of bone length and MicroCT analysis of bone structure (trabecular bone, porosity).
- In vitro studies using bone marrow-derived stem cells to evaluate osteogenesis and osteoclastogenesis; gene expression analysis (gain- and loss-of-function) to identify miR-455 targets.
Main Results:
- miR-455 null mice exhibited significantly increased long bone and vertebral length at 3 weeks of age, with this difference persisting, though diminishing, up to 1 year.
- Increased osteogenesis and decreased osteoclastogenesis/function were observed in miR-455 null mice, correlating with enhanced trabecular bone mass and reduced porosity at 3 weeks.
- Fibroblast growth factor 18 (FGF18) was identified and validated as a direct target gene regulated by miR-455.
Conclusions:
- miR-455 plays a significant role in regulating bone formation and density, particularly during early development.
- The observed bone phenotype in miR-455 null mice is mediated, at least in part, by the regulation of FGF18 expression.
- Targeting the miR-455/FGF18 axis presents a potential therapeutic strategy for modulating bone mass.
