Bone-targeted lncRNA OGRU alleviates unloading-induced bone loss via miR-320-3p/Hoxa10 axis

Ke Wang,Gaozhi Li,Zebing Hu,Lei Dang,Ge Zhang,Yixuan Wang,Lijun Zhang,Shu Zhang,Xinsheng Cao,Fei Shi,Yingjun Tan

doi:10.1038/s41419-020-2574-1

Abstract

Unloading-induced bone loss is a threat to human health and can eventually result in osteoporotic fractures. Although the underlying molecular mechanism of unloading-induced bone loss has been broadly elucidated, the pathophysiological role of long noncoding RNAs (lncRNAs) in this process is unknown. Here, we identified a novel lncRNA, OGRU, a 1816-nucleotide transcript with significantly decreased levels in bone specimens from hindlimb-unloaded mice and in MC3T3-E1 cells under clinorotation-unloading conditions. OGRU overexpression promoted osteoblast activity and matrix mineralization under normal loading conditions, and attenuated the suppression of MC3T3-E1 cell differentiation induced by clinorotation unloading. Furthermore, this study found that supplementation of pcDNA3.1(+)–OGRU via (DSS)6–liposome delivery to the bone-formation surfaces of hindlimb-unloaded (HLU) mice partially alleviated unloading-induced bone loss. Mechanistic investigations demonstrated that OGRU functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of Hoxa10 by competitively binding miR-320-3p and subsequently promote osteoblast differentiation and bone formation. Taken together, the results of our study provide the first clarification of the role of lncRNA OGRU in unloading-induced bone loss through the miR-320-3p/Hoxa10 axis, suggesting an efficient anabolic strategy for osteoporosis treatment.

Highlights

Bone remodeling is a complex process orchestrated by the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption[1]
The expression of candidate long noncoding RNAs (lncRNAs) selected from the microarray assay data according to the fold change in expression was further validated by quantitative real-time polymerase chain reaction (qRT-PCR)
The results showed that NONMMUT068562 was markedly decreased in the clinorotationunloading group, and that this change persisted for at least 72 h in MC3T3-E1 cells (Fig. 1a, b)

Summary

Introduction

Bone remodeling is a complex process orchestrated by the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption[1]. This balance can be regulated by a variety of factors, such as hormones, cytokines, and mechanical stimuli[2]. HLU mice, an established model used to simulate skeletal unloading, show irreversible bone loss via the inhibition of bone formation, and the promotion of bone resorption[5,7,8,9]. To further understand the pathophysiology of unloadinginduced bone loss and identify new biological targets, we selected 2D clinorotation and HLU models for simulating unloading conditions in vitro and in vivo

Methods

Results

Conclusion