Emerging evidence indicates that microRNAs (miRNAs) have important roles in regulating osteogenic differentiation and bone formation. Thus far, no study has established the pathophysiological role for miRNAs identified in human osteoporotic bone specimens. Here we found that elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures. We also found that osteoblast-specific manipulation of miR-214 levels by miR-214 antagomir treatment in miR-214 transgenic, ovariectomized, or hindlimb-unloaded mice revealed an inhibitory role of miR-214 in regulating bone formation. Further, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomir-214, and miR-214 directly targeted ATF4 to inhibit osteoblast activity. These data suggest that miR-214 has a crucial role in suppressing bone formation and that miR-214 inhibition in osteoblasts may be a potential anabolic strategy for ameliorating osteoporosis.

Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.

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Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in development and progression in various types of cancers, but its role in gastric cancer has not been fully elucidated. The purpose of this study was to investigate the levels of miR-146a expression and its function in human gastric cancer. Quantitative real-time polymerase chain reaction was used to detect the levels of miR-146a expression in gastric cancer tissue samples and cell lines. The cell growth rate of MKN-45 gastric cancer cells transfected with miR-146a mimics was examined by MTT assay. The effects of miR-146a on cell cycle and apoptosis were assessed by FACS analyses in MKN-45 cells. Thirty-six of 43 gastric cancer tissue samples (84%) showed decreased expression of miR-146a. We found low expression of miR-146a was correlated with increased tumor size (P = 0.006) and poor differentiation (P = 0.010) in gastric cancer. Overall survival time of patients with high miR-146a expression was significantly longer than that of patients with low expression of miR-146a (P = 0.011). The MTT assay showed that introduction of miR-146a inhibited cell proliferation in MKN-45 cells (P < 0.05). The proportion of apoptotic cells induced by transfection of miR-146a mimics were greater than that induced by transfection of the negative control mimics (11.9 vs. 5.9%). Our results suggested that miR-146a has potential as a novel suppressor gene in gastric cancer and its down-regulation may promote the progression of gastric cancer.