Mechanical stimulation plays an important role in bone remodeling.Exercise-induced mechanical loading enhances bone strength,whereas mechanical unloading leads to bone loss.Increasing evidence has demonstrated that long noncoding RNAs(IncRNAs)play key roles in diverse biological,physiological and pathological contexts.However,the roles of IncRNAs in mechanotransduction and their relationships with bone formation remain unknown.In this study,we screened mechanosensing IncRNAs in osteoblasts and identified Neat1,the most clearly decreased lncRNA under simulated microgravity.Of note,not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations,which were closely associated with osteoblast function.Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading.Neat1 knockout mice displayed disrupted bone formation,impaired bone structure and strength,and reduced bone mass.Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation.In vivo,Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation.Mechanistically,paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 mRNA and downregulation of their translation,thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2,a Smurf1 target.Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation,which provides a paradigm for the function of the lncRNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight-or bedrest-induced bone loss and age-related osteoporosis.

Caizhi Liu;Xingcheng Gao;Yuheng Li;Weijia Sun;Youjia Xu;Yingjun Tan;Ruikai Du;Guohui Zhong;Dingsheng Zhao;Zizhong Liu;Xiaoyan Jin;Yinlong Zhao;Yinbo Wang;Xinxin Yuan;Junjie Pan;Guodong Yuan;Youyou Li;Wenjuan Xing;Guanghan Kan;Yanqing Wang;Qi Li;Xuan Han;Jianwei Li;Shukuan Ling;Yingxian Li

State Key Laboratory of Space Medicine Fundamentals and Application,China Astronaut Research and Training Center,Beijing,China;The Key Laboratory of Aerospace Medicine,Ministry of Education,The Fourth Military Medical University,Xi'an,Shaanxi,China;The Second Affiliated Hospital of Soochow University,Suzhou,Jiangsu,China;College of Life Sciences,Hebei Normal University,Shijiazhuang,Hebei,China;Medical College of Soochow University,Suzhou,Jiangsu,China;Medical School of Southeast University,Nanjing,Jiangsu,China

骨研究（英文版）

[1]Caizhi Liu;Xingcheng Gao;Yuheng Li;Weijia Sun;Youjia Xu;Yingjun Tan;Ruikai Du;Guohui Zhong;Dingsheng Zhao;Zizhong Liu;Xiaoyan Jin;Yinlong Zhao;Yinbo Wang;Xinxin Yuan;Junjie Pan;Guodong Yuan;Youyou Li;Wenjuan Xing;Guanghan Kan;Yanqing Wang;Qi Li;Xuan Han;Jianwei Li;Shukuan Ling;Yingxian Li-.The mechanosensitive IncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention)[J].骨研究（英文版）,2022(02):338-353

Smurf1,Paraspeckles,punctate,paraspeckles,bedrest

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