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Aging-related osteoporosis (OP) is considered a serious public health concern. Approximately 30% of postmenopausal women suffer from OP; more than 40% of them risk fragility fractures. Multiple drugs have been prescribed to treat OP, but they are not ideal because of low cure rates and adverse side effects. miRNA-based gene therapy is a rapidly developing strategy in disease treatment that presents certain advantages, such as large-scale production capability, genetic safety, and rapid effects. miRNA drugs have been used primarily in cancer treatments; they have not yet been reported as candidates for osteoclast-targeted-OP treatment in primates. Their therapeutic efficacy has been limited by several shortcomings, such as low efficiency of selective delivery, insufficient expression levels in targeting cells, and unexpected side effects. Here, we identify miR-141 as a critical suppressor of osteoclastogenesis and bone resorption. The expression levels of miR-141 are positively correlated with BMD and negatively correlated with the aging of bones in both aged rhesus monkeys (Macaca mulatta) and osteoporotic patients. Selective delivery of miR-141 into the osteoclasts of aged rhesus monkeys via a nucleic acid delivery system allowed for a gradual increase in bone mass without significant effects on the health and function of primary organs. Furthermore, we found that the functional mechanism of miR-141 resides in its targeting of two osteoclast differentiation players, Calcr (calcitonin receptors) and EphA2 (ephrin type-A receptor 2 precursor). Our study suggests that miRNAs, such as miR-141, could play a crucial role in suppressing bone resorption in primates and provide reliable experimental evidence for the clinical application of miRNA in OP treatment. © 2018 American Society for Bone and Mineral Research.

Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

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