Identification of the circulating microRNAs from osteoporotic vertebral compression fracture patients

Abstract

Osteoporosis, an age-related metabolic skeletal disease characterized by destruction of bone micro-architecture, decrease of bone quantity, insufficient calcium deposits, and increased bone fragility, results in millions of bone fractures with the vast prevalence in women aged over 50. Considering the established tools for the diagnosis of osteoporosis have multiple limitations in clinical application, the exploration for a novel biochemical molecule identified from osteoporotic individuals are of particular importance to efficient prevention of osteoporosis. These biochemical molecules may also be studied as novel prediction, diagnosis and monitoring tools for osteoporosis treatment. Recent years, the transcriptional regulation in bone remodeling process has been well characterized. However, research gap in understanding the function of circulating miRNAs in this process remains to be fill up. MiRNAs have showed great importance in various types of diseases, including cancer, heart diseases, lung diseases, nervous system disorders and even genetic diseases. MiRNA can be transported into extracellular circulation in several ways including: 1) complex with high-density lipoproteins (HDL) or Ago2 protein; 2) encapsulated with multivesicles; 3) accumulated in apoptotic bodies and 4) packaged within exosomes. The stability of circulating miRNA is not affected by extreme terms including heating, strong-acid/alkali, and repeated freezing and thawing. In addition, the repeatability and consistency of circulating miRNA expression level in similar people makes circulating miRNAs as promising candidates for biomarker. Subsequent studies have carried out for understanding the physiological roles of specific miRNAs in bone disorder. Emerging publications suggest miRNAs as crucial modulator in bone homeostasis. Nevertheless, function of circulating miRNA in osteogenesis process is unclear. Yet, the differential expressed circulating miRNAs in osteoporotic vertebral compression patients remain unknown. Here we found that circulating miR-15b, miR-144, miR-19b and miR-106b were significantly lower expressed in osteoporotic patients than healthy controls. MiR-15b, miR-19b and miR-106b was increased expressed in human mesenchymal stem cells (hMSCs) and MC3T3-E1 cells cultured with osteogenic medium. In addition, osteoblastic differentiation of hMSCs and MC3T3-E1 cells were promoted by the overexpression of miR-15b, miR-19b and miR-106b. Gene of phosphate and tension homology deleted on chromsome ten (PTEN), was directly repressed by miR-19b with concomitant promotion of Runx2 expression, stimulating the phosphorylation of Protein Kinase B (AKT). Circulating miR-19b in aged ovariectomized (OVX) mice was lower expressed compared with young mice. The osteoporotic bone phenotype was alleviated by the injection of chemical modified miR-19b (agomir-miR-19b) in aged OVX mice. Taken together, the circulating miR-19b plays important roles in enhancing osteoblastogenesis, possibly by activating PTEN/pAKT/Runx2 pathway. Our findings reveal a discrepant plasma miR-19b cohort in osteoporotic patients with vertebral fractures and its positive role on osteogenesis. MiR-19b may render a diagnostic tool of biomarkers for osteoporosis and novel molecular therapy targets.