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Original Article | Open Access

HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation

Yuheng Li1,2,, Weijia Sun2,3,, Jianwei Li2, Ruikai Du2, Wenjuan Xing1,2, Xinxin Yuan2, Guohui Zhong1,2, Dingsheng Zhao2, Zizhong Liu2, Xiaoyan Jin2, Junjie Pan2,4, Youyou Li2, Qi Li2, Guanghan Kan2, Xuan Han2, Shukuan Ling5 ( ), Xiqing Sun1( ), Yingxian Li2( )
The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi’an, Shaanxi, China
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
The Center of Space Bio-Medicine, Beijing Institute of Technology, Beijing, China
Medical College of Soochow University, Suzhou, Jiangsu, China
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China

These authors contributed equally: Yuheng Li, Weijia Sun

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Abstract

Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.

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Bone Research
Volume 11,
December 2023
Article number: 53
DOI: 10.1038/s41413-023-00289-2
Cite this article:
Li Y, Sun W, Li J, et al. HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation. Bone Research, 2023, 11: 53. https://doi.org/10.1038/s41413-023-00289-2

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Received: 15 February 2023
Revised: 25 August 2023
Accepted: 28 August 2023
Published: 23 October 2023
© The Author(s) 2023

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