Abstract: Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences
leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs)
affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic
phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density
(BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for
assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679
and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further,
we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures
comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured
bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic
cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of
miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher
microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblastexpressed
microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression
could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone
disorders.