Small non-coding RNAs-based bone regulation and targeting therapeutic strategies

Abstract

Small non-coding RNAs, which are 20-25 nucleotide ribonucleic acids, have emerged as an important transformation in the biological evolution over almost three decades. microRNAs (miRNAs) and short interfering RNAs (siRNAs) are two significant categories of the small RNAs that exert important effects on bone endocrinology and skeletology. Therefore, clarifying the expression and function of these important molecules in bone endocrine physiology and pathology is of great significance for improving their potential therapeutic value for metabolism-associated bone diseases. In the present review, we highlight the recent advances made in understanding the function and molecular mechanism of these small non-coding RNAs in bone metabolism, especially their potentially therapeutic values in bone-related diseases.

Keywords: Bone metabolism; Targeting therapeutics; miRNA; siRNA.

Fig. 1

Schematic gene silencing mechanism of miRNA and siRNA. miRNA gene transcription is executed by RNA polymerase II in the nucleus, leading to the formation of pri-miRNA, and then cleaved by Drosha to form pre-miRNA. Subsequently, the pre-miRNA is transported by Exportin 5 from the nucleus to the cytoplasm. siRNAs, which are exogenous products in origin, are derived directly from the transposon, transgene trigger or virus. After transporting to the cytoplasm, pre-miRNA and long dsRNA are both processed by Dicer to form miRNA and siRNA, separately. Then, both the sense strand of miRNA and siRNA are cleaved by AGO2, a component of RISC. The remaining anti-sense strand of miRNA and siRNA guide the active RISC to their target mRNA with partial complementarity and complementarity, respectively, leading to different target gene silencing effects. AGO2, Argonaute 2. RISC, RNA-induced silencing complexes.

Fig. 2

Schematic summary of miRNA role in osteoblast and osteoclast differentiation. (a) miRNAs regulating osteoblast differentiation, proliferation and function. A cohort of transcription factors tightly regulate osteoblast commitment, such as Runx2, Osterix, ATF4 and β-catenin, from osteoprogenitors during skeletal development. (b) miRNAs effect various of molecules related to osteoclast commitment, such as RANKL and M-CSF, leading to changes in osteoclast activity in vitro as well as alterations in bone resorption in vivo. ATF4, activating transcription factor 4. HOXA10, homeobox a10. FZD3, Frizzled-3. LRP5, lipoprotein-receptor-related protein 5. M-CSF, macrophage colony-stimulating factor. Runx2, runt-related transcription factor 2. OPG, osteopontegrin. PTEN, phosphatase and tensin homologue. RANKL, receptor activator NFκB ligand. STAT1, signal transducer and activator of transcription 1. SATB2, special AT-rich sequence-binding protein 2.