The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblast differentiation in vivo. RNF40 expression is essential for early stages of lineage specification, but is dispensable in mature osteoblasts. Paradoxically, while osteoblast-specific RNF40 deletion led to impaired bone formation, it also resulted in increased bone mass due to impaired bone cell crosstalk. Loss of RNF40 resulted in decreased osteoclast number and function through modulation of RANKL expression in OBs. Mechanistically, we demonstrate that Tnfsf11 (encoding RANKL) is an important target gene of H2B monoubiquitination. These data reveal an important role of RNF40-mediated H2B monoubiquitination in bone formation and remodeling and provide a basis for exploring this pathway for the treatment of conditions such as osteoporosis or cancer-associated osteolysis.

组蛋白泛素化在指导细胞谱系规范中的作用知之甚少。我们之前的工作表明组蛋白 2B 泛素连接酶 RNF40 在体外控制成骨细胞分化中的作用。在这里，我们证明 RNF40 在控制体内成骨细胞分化方面具有阶段依赖性功能。RNF40 表达对于谱系规范的早期阶段是必不可少的，但在成熟的成骨细胞中是可有可无的。矛盾的是，虽然成骨细胞特异性 RNF40 缺失导致骨形成受损，但由于骨细胞串扰受损，它也导致骨量增加。通过调节 OB 中的 RANKL 表达，RNF40 的缺失导致破骨细胞数量和功能减少。从机制上讲，我们证明了 Tnfsf11（编码RANKL）是H2B单泛素化的重要靶基因。这些数据揭示了 RNF40 介导的 H2B 单泛素化在骨形成和重塑中的重要作用，并为探索该途径治疗骨质疏松症或癌症相关的骨溶解等疾病提供了基础。