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.

骨髓间充质干细胞（BMSC）成骨分化和成骨细胞功能在骨形成中发挥着关键作用，骨形成是一个高度调控的过程。长非编码 RNA (lncRNA) 在多种生物过程中发挥多种功能，包括 BMSC 成骨分化。尽管一些研究报道HOX转录反义RNA（HOTAIR）参与BMSC成骨分化，但其对体内骨形成的影响仍不清楚。在这里，通过构建BMSC（Prx1-HOTAIR）和成骨细胞（Bglap-HOTAIR）特异性过表达HOTAIR的转基因小鼠，我们发现Prx1-HOTAIR和Bglap-HOTAIR转基因小鼠在体内表现出不同的骨表型。具体来说，Prx1-HOTAIR 小鼠显示骨形成延迟，而 Bglap-HOTAIR 小鼠显示骨形成增加。HOTAIR 抑制 BMSC 成骨分化，但在体外促进成骨细胞功能。此外，我们发现 HOTAIR 主要位于 BMSC 的细胞核和成骨细胞的细胞质中。HOTAIR 在 BMSC 成骨分化过程中表现出核细胞质易位模式。我们首先发现 RNA 结合蛋白人类抗原 R (HuR) 负责 HOTAIR 核质易位。HOTAIR 对于成骨细胞功能至关重要，细胞质 HOTAIR 与 miR-214 结合并充当 ceRNA，以增加 Atf4 蛋白水平和成骨细胞功能。Bglap-HOTAIR 小鼠（而非 Prx1-HOTAIR 小鼠）显示出减轻由卸载引起的骨丢失。该研究揭示了HOTAIR在BMSC成骨分化和骨形成中的时空调节的重要性，为骨丢失的精确调节靶点提供了新的见解。