Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis

作者：X. R. Wang, X. R. Wang, Fangji Luo, Guiqiang Miao, Boyuan Zheng, Chenhao Xu, Vincent Kam Wai Wong, Yi Peng, Rong Zeng, Jinzhu Pang, Xuguang Zhang, Zhenyu Ju, Zhengang Zha, Xiaogang Wang, Xiaogang Wang, Xiaofei Zheng, Huan‐Tian Zhang · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70496 · 被引用次数：1 · 研究领域：Protein Degradation and Inhibitors、Chromatin Remodeling and Cancer、Histone Deacetylase Inhibitors Research

BACKGROUND: Epigenetic regulation plays a crucial role in skeletal degenerative diseases, including osteoporosis. As an epigenetic reader, bromodomain protein 4 (Brd4) is known as a key driver of gene activation; however, its role in maintaining skeletal homeostasis remains largely unknown. METHODS: We examined Brd4 expression in bone specimens from osteoporotic patients and mouse models, and generated two types of Brd4 conditional knockout mice using Lyz2-Cre and Ctsk-Cre systems. Bone mass, osteoclast differentiation, and metabolic activity were assessed under physiological and pathological conditions, including ovariectomy and lipopolysaccharide (LPS) challenge. Mechanistic analyses were performed using transcriptomic screening, gene overexpression, and pharmacological interventions. RESULTS: Brd4 expression was markedly elevated in bones from osteoporotic patients and mice compared with normal controls. Deletion of Brd4 increased basal bone mass and prevented bone loss induced by ovariectomy or LPS, primarily by suppressing osteoclastogenesis through inhibition of glycolysis. Unbiased screening identified solute carrier family 9 member B2 (Slc9b2) as a downstream effector of Brd4. Overexpression of Slc9b2 partially rescued the impaired osteoclastogenesis caused by Brd4 depletion. Moreover, phosphatidylserine-containing nanoliposomes loaded with Brd4-targeting PROTACs (e.g., dBET6) effectively suppressed osteoclastogenesis and alleviated pathological bone loss. CONCLUSIONS...