MicroRNA-874-3p is a Potential Contributor to Primary Hyperparathyroidism-Induced Osteoporosis.

Background: Dysregulation of microRNAs contributes to bone diseases. However, the microRNAs involved in primary hyperparathyroidism (PHPT)-induced osteoporosis remain unknown. Methods: The parathyroid tissue samples were obtained from PHPT patients with or without osteoporosis (n = 5/group) during parathyroid resection and subjected to high throughput microRNA sequencing. The differentially expressed microRNAs were identified and further verified using qRT-PCR. Alizarin Red Staining was performed to detected the osteogenic differentiation. Gain- and loss-of-function assays were performed to investigate the role of miR-874-3p, which was upregulated in PHPT patients with osteoporosis, in human mesenchymal stem cells (hMSCs) undergoing osteoblastic differentiation. Results: We identified 32 significantly upregulated and 18 significantly downregulated microRNAs in PHPT patients with osteoporosis. miR-874-3p was increased in PHPT osteoporosis patients, meanwhile, miR-874-3p in parathyroid tissue and peripheral blood extracellular vesicles of PHPT osteoporosis mice were increased. The miR-874-3p level was remarkably elevated in hMSCs grown in osteogenic medium. Overexpression of miR-874-3p repressed the hMSC osteogenic differentiation and reduced the osteogenic marker expression in hMSCs, whereas miR-874-3p inhibitor showed a contrasting effect. The results of the dual luciferase reporting system showed that miR-874-3p could reduce the luciferase activity of wild-type FTO-WT-3 '-UTR. However, there was no significant change in the luciferase activity of the mutant compared with the control group. Conclusion: MiR-874-3p might specifically binds to FTO suppress osteogenic differentiation of hMSCs, thereby contributing to the development of osteoporosis in PHPT patients.