The microRNA-455 null mouse shows dysregulated bone turnover

Niu, LZ; Swingler, TE; Suelzu, C; Ersek, A; Orriss, IR; Barter, MJ; Hayman, DJ; Young, DA; Horwood, N; Clark, IM

Abstract

A wide range of specific microRNAs have been shown to have either positive or negative effects on osteoblast differentiation and function, with consequent changes in postnatal bone mass. A number of specific targets have been identified. We previously used CrispR-Cas9 to make a miR-455 null mouse, characterizing a behavioral phenotype with age. The current study identifies a bone phenotype, starting in younger animals. At 3 weeks of age, the miR-455 null mice (both male and female) display increased length of both long bones and vertebrae and, while this difference diminishes across 1 year, it remains significant. Increased bone formation in vivo is mirrored by an increase in osteogenesis from bone marrow-derived stem cells in vitro. This is accompanied by a decrease in osteoclastogenesis and osteoclast function. MicroCT analyses show increased trabecular bone and less porosity/decreased separation in the miR-455 null mouse, suggesting a more dense and stronger bone at 3 weeks of age; these differences normalize by 1 year. Gain-of-function and loss-of-function datasets show that FGF18 expression is regulated by miR-455 and FGF18 was validated as a direct target of miR-455. The regulation of FGF18 by miR-455 is a likely mediator of its effect on bone. MicroRNAs are small molecules that have profound effects on the production of proteins and therefore on the function of cells and animal physiology. We made a mouse that lacks a specific microRNA, microRNA-455. This mouse has an increase in bone length from 3 weeks of age. There is an increase in bone formation by bone-forming cells (osteoblasts) and a decrease in bone loss (mediated by osteoclasts). While several genes/proteins are altered by the absence of microRNA-455, a factor called fibroblast growth factor 18 (FGF18) is increased. This is likely to be a key mediator of the impact of microRNA-455 on bone.

Citation

Niu, L., Swingler, T., Suelzu, C., Ersek, A., Orriss, I., Barter, M., Hayman, D., Young, D., Horwood, N., & Clark, I. (2025). The microRNA-455 null mouse shows dysregulated bone turnover. JBMR Plus, 9(3), https://doi.org/10.1093/jbmrpl/ziaf007

• Journal Article Type: Article
• Acceptance Date: Jan 9, 2025
• Online Publication Date: Jan 12, 2025
• Publication Date: 2025
• Deposit Date: Mar 20, 2025
• Publicly Available Date: Mar 20, 2025
• Print ISSN: 2473-4039
• Electronic ISSN: 2473-4039
• Publisher: American Society for Bone and Mineral Research
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 3
• DOI: https://doi.org/10.1093/jbmrpl/ziaf007
• Keywords: microRNA; miR-455; null mouse; bone; FGF18; CORTICAL BONE; DIFFERENTIATION; GROWTH; DICER; CHONDROGENESIS; PROLIFERATION; OSTEOGENESIS; CHONDROCYTE; RESORPTION; CELLS