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; Xinquan Jiang

doi:10.1038/s41467-023-37116-5

BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism

Nat Commun. 2023 Mar 14;14(1):1413. doi: 10.1038/s41467-023-37116-5.

Authors

Jiahui Du^#^{1

2

3}, Yili Liu^#^{1

2

3}, Xiaolin Wu^#^{1

2

3}, Jinrui Sun^{1

2

3}, Junfeng Shi^{1

2

3}, Hongming Zhang^{1

2

3}, Ao Zheng^{1

2

3}, Mingliang Zhou^{4

5

6}, Xinquan Jiang^{7

8

9}

Affiliations

¹ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
² College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China.
³ National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, 200011, China.
⁴ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. mingliangzhou@aliyun.com.
⁵ College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China. mingliangzhou@aliyun.com.
⁶ National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, 200011, China. mingliangzhou@aliyun.com.
⁷ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. xinquanjiang@aliyun.com.
⁸ College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China. xinquanjiang@aliyun.com.
⁹ National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, 200011, China. xinquanjiang@aliyun.com.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Resorption* / metabolism
Cell Cycle Proteins / metabolism
Chromatin Assembly and Disassembly
Feedback
Forkhead Transcription Factors / metabolism
Humans
Nuclear Proteins / metabolism
Osteoclasts / metabolism
Osteogenesis
Repressor Proteins / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

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