Abstract
ABSTRACTMicroRNAs (miRNAs) play essential roles in regulating bone formation and homeostasis. Genomic variations within miRNA target sites may therefore be important sources of genetic differences in osteoporosis risk. The function of CCDC170 in bone biology is still unclear. To verify the function of CCDC170, we knocked down CCDC170 in cells and mice and searched for miRNA recognition sites within CCDC170 using the TargetScan, miRNASNP, and miRBase databases. In this study, our results demonstrated that CCDC170 plays an important role in the positive regulation of bone formation. MiR-153-3p, miR-374b-3p, miR-4274, miR-572 and miR-2964a-5p inhibited CCDC170 expression in an allele-specific manner by binding GWAS lead SNPs rs6932603, rs3757322 and rs3734806. These findings may improve our understanding of the association between CCDC170, miRNAs, GWAS lead SNPs, and osteoporosis pathogenesis and may provide a potential therapeutic target for osteoporosis therapy.
Highlights
Osteoporosis is a common complex disease defined by bone mineral density (BMD) that is highly heritable, with heritability estimates of 0.5–0.85 (Ralston and Uitterlinden, 2010)
MiRNAs differentially regulated expression of the allele variants of genome-wide association studies (GWASs) lead Single-nucleotide polymorphism (SNP) we tested a biological model in which miR-153-3p differentially regulated the C/T allele variants of rs6932603 in CCDC170
These results indicated that miR153-3p, miR-374b-3p, miR-4274, miR-572 and miR-2964a-5p inhibited CCDC170 expression by differentially binding three GWAS lead SNPs
Summary
Osteoporosis is a common complex disease defined by bone mineral density (BMD) that is highly heritable, with heritability estimates of 0.5–0.85 (Ralston and Uitterlinden, 2010). With increased age and hormonal changes, the body’s bone mass decreases. When bone mass decreases and bone fragility increases, fractures and osteoporosis will eventually occur (Albagha and Ralston, 2003). Fractures due to osteoporosis are a major public health burden (Cauley, 2013). This has led to an increased effort in developing more effective means of treating and preventing bone disease (Sabik and Farber, 2017). Discovering genetically variable loci and clarifying their biological functions in BMD variations are important to understanding the etiology of osteoporosis
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