The DLEU2–miR-15a–16-1 Cluster Is a Determinant of Bone Microarchitecture and Strength in Postmenopausal Women and Mice

This study explores how select microRNAs (miRNAs) influence bone structure in humans and in transgenic mice. In trabecular bone biopsies from 84 postmenopausal women (healthy, osteopenic, and osteoporotic), we demonstrate that <i>DLEU2</i> (deleted in lymphocytic leukemia 2)-encoded <i>miR-15a-5p</i> is strongly positively associated with bone mineral density (BMD) at different skeletal sites. In bone transcriptome analyses, <i>miR-15a-5p</i> levels correlated positively with the osteocyte characteristic transcripts <i>SOST</i> (encoding sclerostin) and <i>MEPE</i> (Matrix Extracellular Phosphoglycoprotein), while the related <i>miR-15b-5p</i> showed a negative association with BMD and osteoblast markers. The data imply that these miRNAs have opposite roles in bone remodeling with distinct actions on bone cells. Expression quantitative trait loci (eQTL) variants confirmed earlier <i>DLEU2</i> associations. Furthermore, a novel variant (rs12585295) showed high localization with transcriptionally active chromatin states in osteoblast primary cell cultures. The supposition that <i>DLEU2</i>-encoded miRNAs have an important regulatory role in bone remodeling was further confirmed in a transgenic mice model showing that <i>miR-15a/16-1</i>-deleted mice had significantly higher percentage bone volume and trabecular number than the wild type, possibly due to prenatal actions. However, the three-point mechanical break force test of mice femurs showed a positive correlation between strength and <i>miR-15a-5p/miR-16-5p</i> levels, indicating differential effects on cortical and trabecular bone. Moreover, these miRNAs appear to have distinct and complex actions in mice prenatally and in adult humans, impacting BMD and microstructure by regulating bone cell transcription. However, detailed interactions between these miRNAs and their downstream mechanisms in health and disease need further clarification.