miR-182 is a negative regulator of osteoblast proliferation, differentiation and skeletogenesis through targeting FoxO1
- Authors
- Kim, K.M., Park, S.J., Jung, S.H., Kim, E.J., Jogeswar, G., Ajita, J., Rhee, Y., Kim, C.H., and Lim, S.K.
- ID
- ZDB-PUB-120326-20
- Date
- 2012
- Source
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 27(8): 1669-1679 (Journal)
- Registered Authors
- Jung, Seung-Hyun
- Keywords
- miR-182, microRNA, osteoblast, mesenchymal stem cell, FoxO1
- MeSH Terms
-
- 3' Untranslated Regions/genetics
- Animals
- Apoptosis/genetics
- Base Sequence
- Bone and Bones/metabolism
- Cell Differentiation/genetics*
- Cell Line
- Cell Proliferation
- Cell Survival
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism*
- Gene Expression Regulation
- Mesenchymal Stem Cells/metabolism
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- Models, Animal
- Molecular Sequence Data
- Osteoblasts/cytology*
- Osteoblasts/metabolism
- Osteogenesis/genetics*
- Skull/cytology
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 22431396 Full text @ J. Bone Miner. Res.
Uncontrolled oxidative stress impairs bone formation and induces age-related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR-182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR-182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, while in vivo overexpression of miR-182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR-182, and restoration of FoxO1 expression in miR-182 overexpressing osteoblasts rescued them from the inhibitory effects of miR-182. These results indicate that miR-182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR-182 could be of therapeutic value.