| Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis |
| 论文作者 |
Wang, XH; Luo, FJ; Miao, GQ; Zheng, BY; Xu, CH; Wong, VKW; Peng, YS; Zeng, R; Pang, JZ; Zhang, XG; Ju, ZY; Zha, ZG; Wang, XG; Zheng, XF; Zhang, HT |
| 期刊/会议名称 |
CLINICAL AND TRANSLATIONAL MEDICINE |
| 论文年度 |
2025 |
| 论文类别 |
|
| 摘要 |
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 Brd4 serves as a crucial regulator of osteoclast metabolism and differentiation. Targeting Brd4 represents a promising therapeutic strategy for the prevention and treatment of osteoporosis and pathological bone loss. |
| 卷 |
15 |
| 影响因子 |
6.8 |
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