BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism.

Abstract

Bromodomain-containing protein 9 (BRD9), a component of non-canonical BAF chromatin remodeling complex, has been identified as a critical therapeutic target in hematological diseases. Despite the hematopoietic origin of osteoclasts, the role of BRD9 in osteoclastogenesis and bone diseases remains unresolved. Here, we show Brd9 deficiency in myeloid lineage enhances osteoclast lineage commitment and bone resorption through downregulating interferon-beta (IFN-β) signaling with released constraint on osteoclastogenesis. Notably, we show that BRD9 interacts with transcription factor FOXP1 activating Stat1 transcription and IFN-β signaling thereafter. Besides, function specificity of BRD9 distinguished from BRD4 during osteoclastogenesis has been evaluated. Leveraging advantages of pharmacological modulation of BRD9 and flexible injectable silk fibroin hydrogel, we design a local deliver system for effectively mitigating zoledronate related osteonecrosis of the jaw and alleviating acute bone loss in lipopolysaccharide-induced localized aggressive periodontitis. Overall, these results demonstrate the function of BRD9 in osteoclastogenesis and its therapeutic potential for bone diseases.

• Authors: Jiahui Du, Yili Liu, Xiaolin Wu, Jinrui Sun, Junfeng Shi, Hongming Zhang, Ao Zheng, Mingliang Zhou, Xinquan Jiang
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 1413 (03 14 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 36918560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Cell Cycle Proteins
• Forkhead Transcription Factors
• Nuclear Proteins
• Repressor Proteins
• Transcription Factors

Topics

• Humans
• Bone Resorption (metabolism)
• Cell Cycle Proteins (metabolism)
• Chromatin Assembly and Disassembly
• Feedback
• Forkhead Transcription Factors (metabolism)
• Nuclear Proteins (metabolism)
• Osteoclasts (metabolism)
• Osteogenesis
• Repressor Proteins (metabolism)
• Transcription Factors (genetics, metabolism)