Mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention

Mechanical stimulation plays an important role in bone remodeling. Exercising induced mechanical loading enhances bone strength and mechanical unloading leads to bone loss. Increasing evidence demonstrates that lncRNA plays key roles in diverse biological, physiological and pathological contexts. However, the role of lncRNA in mechanotransduction and its relation with bone formation remains unknown. In this study, we screened the mechanosensing lncRNAs in osteoblasts and identified Neat1, the most obviously decreased lncRNA under simulated microgravity. It is surprising to find that not only Neat1 expression but the specific paraspeckle structure formed by Neat1 are sensitive to different mechanical stimulations, which are closely related with the function of osteoblast. Paraspeckle exhibits small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice exhibited disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts blunts 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 promote nuclear retention of E3 ubiquitin ligase Smurf1 mRNA, down-regulation of their translation, thus inhibiting ubiquitination degradation of osteoblast master transcription factor Runx2, one of the Smurf1 targets. Our study revealed that Neat1 plays an indispensable role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of lncRNA assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight or bedrest induced bone loss and aged osteoporosis.