Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene’s transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2’s protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.

缺失、小或同源异型 (ASH1L) 是一种组蛋白赖氨酸甲基转移酶，通常作为控制细胞命运的转录激活剂发挥作用。迄今为止，其在骨稳态和破骨细胞分化中的生理相关性仍然难以捉摸。在这里，通过有条件地删除小鼠破骨细胞祖细胞中的Ash1l，我们发现 ASH1L 缺陷会导致体内和体外骨质疏松症和破骨细胞生成增强。从机制上讲，ASH1L 结合 Src 同源 3 和富含半胱氨酸结构域 2 ( Stac2 )的启动子，并通过组蛋白 3 赖氨酸 4 (H3K4) 三甲基化修饰增加基因转录，从而增强 STAC2 对核因子 kB 配体受体激活剂的保护。 RANKL）在破骨细胞形成过程中引发炎症。总的来说，我们展示了第一个证据来证明 ASH1L 是破骨细胞生成过程中的关键检查点。这项工作为我们对 ASH1L 在骨稳态中的生物学功能的理解提供了新的线索，从而为骨质疏松症或炎症性骨疾病的治疗提供了有价值的治疗靶点。