Abstract
Recent studies have confirmed that microRNAs and lncRNAs can affect bone cell differentiation and bone formation. In this study, miR-139-3p was upregulated in the femurs of hindlimb unloading mice and MC3T3-E1 cells under simulated microgravity; this effect was related to osteoblast differentiation and apoptosis. Silencing miR-139-3p attenuated the suppression of differentiation and the promotion of MC3T3-E1 cell apoptosis induced by simulated microgravity. ELK1 is a target of miR-139-3p and is essential for miR-139-3p to regulate osteoblast differentiation and apoptosis. An osteoblast differentiation-related lncRNA that could interact with miR-139-3p (lncRNA ODSM) was identified in MC3T3-E1 cells under simulated microgravity. Further investigations demonstrated that lncRNA ODSM could promote MC3T3-E1 cell differentiation. Therefore, this research was the first to reveal the critical role of the lncRNA ODSM/miR-139-3p/ELK1 pathway in osteoblasts, and these findings suggest the potential value of miR-139-3p in osteoporosis diagnosis and therapy.
Highlights
Osteoporosis is related to several risk factors, including hormone fluctuation, nutrition, and inflammatory and mechanical stress[1,2,3]
MiR-139-3p is upregulated in the femurs of hindlimb unloading mice and MC3T3-E1 cells under simulated microgravity To explore the expression and significance of miRNAs in mouse osteoblasts under simulated microgravity, hindlimb unloaded (HU) mice and cells under clinorotation conditions were selected as models
(see figure on previous page) Fig. 4 MiR-139-3p directly targets ELK1 in MC3T3-E1 cells, and ELK1 is sensitive to simulated microgravity. a Schematic representation of the luciferase reporter containing ELK1 3′UTR wild-type ELK1 3′UTR sequence (WT) or ELK1 3′UTR mutant sequence (MUT). b The luciferase activity of the ELK1 WT and ELK1 MUT reporter in 293T cells treated with mimic-139, inhibitor-139 or the corresponding controls for 24 h (N = 3). c mRNA expression of ELK1 in osteoblasts treated with mimic-139, inhibitor-139 or the corresponding controls for 48 h (N = 3). d Protein levels of ELK1 and pELK1 in osteoblasts (N = 3). e Immunostaining analysis of the expression levels of ELK1 in osteoblasts (N = 3)
Summary
Osteoporosis is related to several risk factors, including hormone fluctuation, nutrition, and inflammatory and mechanical stress[1,2,3]. Bone loss induced by microgravity is similar to osteoporosis in that bone mass is remarkably decreased, and the microarchitectures of the bone are markedly altered. Bone loss induced by microgravity is a critical phenomenon occurring in humans; this process is the most serious threat to astronauts’ health during spaceflight[3,4,5]. Hindlimb unloading animal models and human bed-rest studies are most commonly conducted using in vivo models, which mimic the lack of weight-bearing loads on bones and cephalic fluid shifts in spaceflight[6,7]. In vitro simulators of microgravity utilize mainly clinostat, random positioning machines or rotary wall vessels, which are used to study cell responses to conditions lacking weight-bearing forces[8,9,10]
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