Role of microRNA in bone formation

Role of microRNA in bone formation

Bone is a dynamic tissue that undergoes life-long remodeling regulated by the tight coupling of bone resorption and bone formation. Aside from the well-documented regulatory mechanism of osteoblast-directed osteoclastic bone resorption, accumulating evidence indicates that osteoclasts in turn regulate osteoblastic bone formation either by direct cell–cell contact or indirectly via cytokines. However, it is unclear whether there are other efficient ‘paracrine’ approaches for the osteoclast-toosteoblast communication.
 
MicroRNAs (miRNAs) are B22-nucleotide (nt) noncoding RNAs involved in the regulation of gene expression to coordinate a broad spectrum of biological processes. A series of miRNAs has been characterized to regulate osteogenic activity and osteoblastic bone formation, and the dysregulation of these miRNAs has been linked with the skeletal disorders involving a reduction in bone formation.
 
Moreover, recent studies have demonstrated that miRNAs are presented in body fluid, for example, serum, and they are transported in extracellular vesicles, for example, exosomes, unveiling their novel function as extracellular signals between cells and their extracellular matrix. However, there is a lack of functional miRNAs identified as intercellular signals between osteoclasts and osteoblasts.
 
MiR-214-3p, a vertebrate-specific member of miRNA precursors, is reported to be involved in the regulation of hepatic gluconeogenesis. MiR-214-3p also has a crucial role in skeletal disorders. MiR-214-3p has been shown to suppress osteogenic differentiation of C2C12 myoblast cells by targeting Osterix, an osteoblast-specific transcription factor.
 
Authors previous study also identified that miR-214-3p could target ATF4, an important osteogenic transcriptional factor, to suppress bone formation. Furthermore, miR-214-3p promotes osteoclastogenesis through PI3K/Akt pathway via targeting phosphatase and tensin homologue (PTEN).
 
They examined the expression of bone metabolism-related miRNAs in bone specimens and serum exosomes from elderly bone-fracture women as well as ageing ovariectomized (OVX) mice and show that increased osteoclastic miR-214-3p level associates with both elevated serum exosomal miR-214-3p level and reduced bone formation.
 
Researchers  present in vitro and in vivo evidence to demonstrate that osteoclast-derived exosomal miR-214-3p could transfer to osteoblasts to inhibit osteoblastic bone formation.
 
Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214-3p and reduced bone formation that is rescued by osteoclast-targeted antagomir-214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214-3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo.
 
Moreover, they show that osteoclast-targeted antagomir-214-3p treatment could promote bone formation in ageing OVX mice. Collectively, these results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation.

http://www.nature.com/ncomms/2016/160307/ncomms10872/full/ncomms10872.html

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