2. Academic Validation
  3. Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis

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

  • Clin Transl Med. 2025 Oct;15(10):e70496. doi: 10.1002/ctm2.70496.
Xiaohe Wang 1 2,  Fangji Luo 1,  Guiqiang Miao 3,  Boyuan Zheng 1,  Chenhao Xu 1,  Vincent Kam Wai Wong 4,  Yuanshu Peng 5,  Rong Zeng 5,  Jinzhu Pang 6,  Xuguang Zhang 6,  Zhenyu Ju 1,  Zhengang Zha 1,  Xiaogang Wang 7,  Xiaofei Zheng 1,  Huan-Tian Zhang 1
Affiliations

Affiliations

  • 1 Department of Bone and Joint Surgery, The First Affiliated Hospital of Jinan University & Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Department of Orthopedics, Foshan Fosun Chancheng Hospital, Foshan Clinical Medical School of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China.
  • 4 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macao, SAR, China.
  • 5 Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, Guangdong, China.
  • 6 Mengniu Institute of Nutrition Science, Global R&D Innovation Center, Inner Mongolia Mengniu Dairy (Group), Shanghai Institute of Nutrition and Health, the Chinese Academy of Sciences, Shanghai, China.
  • 7 Department of Orthopedics, Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
PMID: 41115147 DOI: 10.1002/ctm2.70496
Abstract

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.

Key points: Brd4 is highly expressed in osteoporotic patients and Animals. Brd4 is crucial for glycolysis-mediated OC differentiation. The loss of Brd4 in bone marrow monocytes or osteoclasts increases basal bone mass and prevents pathological bone loss. Slc9b2 is a novel target of Brd4 in mediating osteoclastogenesis. Targeting Brd4 by dBET6@PSLs could alleviate osteoporosis progression.

Keywords

Brd4; Slc9b2; osteoclastogenesis; osteoporosis.

Figures
Products