ArticleClinical and translational medicine2025
Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis.
Article in Clinical and translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Glycolysis in bone remodeling: from energy supply to signaling regulation.Molecular biology reports · 2026Review
- Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis.Clinical and translational medicine · 2025Article
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Authors and funding
15 authors.
Funding
Abstract
backgroundEpigenetic 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.
methodsWe 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.
resultsBrd4 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.
conclusionsBrd4 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.