BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism

Jiahui Du, Yili Liu, Xiaolin Wu, Jinrui Sun, Junfeng Shi, Hongming Zhang, Ao Zheng, Mingliang Zhou () and Xinquan Jiang ()
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Jiahui Du: Shanghai Jiao Tong University School of Medicine
Yili Liu: Shanghai Jiao Tong University School of Medicine
Xiaolin Wu: Shanghai Jiao Tong University School of Medicine
Jinrui Sun: Shanghai Jiao Tong University School of Medicine
Junfeng Shi: Shanghai Jiao Tong University School of Medicine
Hongming Zhang: Shanghai Jiao Tong University School of Medicine
Ao Zheng: Shanghai Jiao Tong University School of Medicine
Mingliang Zhou: Shanghai Jiao Tong University School of Medicine
Xinquan Jiang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37116-5

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