Suppression of Bone Resorption by miR-141 in Aged Rhesus Monkeys

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.

The roles of miRNA, lncRNA and circRNA in the development of osteoporosis

“…miR-141 has been identified as a quintessential negative inhibitor of osteoclastogenesis and bone resorption. The functional mechanism involves its targeting of two osteoclast differentiation factors, calcitonin receptor (Calcr) and ephrin A receptor 2 precursor (EphA2) [84]. Recent experiments have shown that oleanolic acid, a new drug that can be used to treat osteoporosis, inhibits RANKL-induced osteoclastogenesis through the ERα/ miR-503/RANK signaling pathway in RAW264.7 cells [85].…”

“…miR-141 has been identified as a quintessential negative inhibitor of osteoclastogenesis and bone resorption. The functional mechanism involves its targeting of two osteoclast differentiation factors, calcitonin receptor (Calcr) and ephrin A receptor 2 precursor (EphA2) [ 84 ].…”

Involvement of Noncoding RNAs in the Differentiation of Osteoclasts

“…Ephrin type-A receptor 2 (EphA2) is suggested to be a miR-141 target in rhesus monkey osteoclasts [ 52 ]. Excessive expression of EphA2 in OCPs induces osteoclast differentiation.…”

MicroRNAs: Key Regulators to Understand Osteoclast Differentiation?

“…EphrinA2 expression is rapidly induced in a c-Fos-dependent manner and cleaved by metalloproteinases to release an active soluble form able to interact with its receptor EphA2, enhancing osteoclastogenesis (55). In rhesus monkey BMMs EphA2 is a potential target of miR-141 (56). OC differentiation and bone resorption are suppressed in vitro by miR-141, and in vivo using repeated injections of an OC-targeted delivery system into aged monkeys (56).…”

“…In rhesus monkey BMMs EphA2 is a potential target of miR-141 (56). OC differentiation and bone resorption are suppressed in vitro by miR-141, and in vivo using repeated injections of an OC-targeted delivery system into aged monkeys (56). The calcitonin receptor (CALCR) is also a target of miR-141 in rhesus OCs.…”