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Suppression of Bone Resorption by miR-141 in Aged Rhesus Monkeys
Shihua Yang1,2, Wenhui Zhang1,2, Mingxiang Cai3
1College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Abstract:
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.
Insights
MicroRNA-141 (miR-141) effectively suppresses bone loss in aging-related osteoporosis by targeting osteoclast activity. This study demonstrates miR-141
Area of Science:
- Molecular biology
- Genetics
- Endocrinology
Background:
- Aging-related osteoporosis (OP) poses a significant public health challenge, with current treatments having limitations.
- MicroRNA (miRNA)-based gene therapy offers a promising alternative for OP treatment, but challenges in targeted delivery and efficacy persist.
- Existing therapies for OP lack optimal cure rates and can cause adverse side effects.
Purpose of the Study:
- To identify novel therapeutic targets for aging-related osteoporosis.
- To investigate the potential of microRNA-141 (miR-141) as a therapeutic agent for osteoclast-targeted OP treatment.
- To evaluate the efficacy and safety of miR-141 delivery in primate models of osteoporosis.
Main Methods:
- Identification of miR-141 as a suppressor of osteoclastogenesis and bone resorption.
- Correlation analysis of miR-141 expression with bone mineral density (BMD) and bone aging in aged rhesus monkeys and osteoporotic patients.
- Selective delivery of miR-141 into osteoclasts of aged rhesus monkeys using a nucleic acid delivery system.
- Investigation of miR-141's molecular mechanism by identifying its targeting of Calcr and EphA2.
Main Results:
- miR-141 expression positively correlates with BMD and negatively with bone aging in both aged rhesus monkeys and human patients.
- Selective delivery of miR-141 in aged rhesus monkeys led to increased bone mass without adverse effects on major organs.
- miR-141 targets Calcitonin Receptor (Calcr) and Ephrin Type-A Receptor 2 (EphA2) to suppress osteoclast differentiation and function.
Conclusions:
- miR-141 is a critical suppressor of osteoclastogenesis and bone resorption, showing therapeutic potential for osteoporosis.
- miRNA-based therapy, specifically using miR-141, offers a viable strategy for treating aging-related osteoporosis in primates.
- This study provides strong experimental evidence supporting the clinical application of miR-141 in managing osteoporosis.
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