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BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism

Jiahui Du1,2,3, Yili Liu1,2,3, Xiaolin Wu1,2,3

  • 1Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.

Nature Communications
|March 15, 2023
PubMed

Insights

Bromodomain-containing protein 9 (BRD9) regulates bone cell formation and function. Targeting BRD9 offers a new therapeutic strategy for bone diseases like osteonecrosis of the jaw and aggressive periodontitis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Bone Biology

Background:

  • Bromodomain-containing protein 9 (BRD9) is part of the non-canonical BAF chromatin remodeling complex and a therapeutic target in hematological diseases.
  • The role of BRD9 in osteoclastogenesis and bone diseases is currently unknown, despite osteoclasts originating from hematopoietic cells.

Purpose of the Study:

  • To investigate the role of BRD9 in osteoclastogenesis and bone diseases.
  • To evaluate BRD9 as a potential therapeutic target for bone-related conditions.

Main Methods:

  • Investigated the effects of Brd9 deficiency in myeloid lineage on osteoclastogenesis and bone resorption.
  • Examined the interaction between BRD9 and transcription factor FOXP1.
  • Assessed the function specificity of BRD9 compared to BRD4 in osteoclastogenesis.
  • Developed a local delivery system using pharmacological BRD9 modulation and silk fibroin hydrogel.

Main Results:

  • Brd9 deficiency in myeloid cells enhances osteoclast lineage commitment and bone resorption by downregulating interferon-beta (IFN-β) signaling.
  • BRD9 interacts with FOXP1 to activate Stat1 transcription and subsequent IFN-β signaling.
  • BRD9 exhibits functional specificity distinct from BRD4 during osteoclastogenesis.
  • The developed delivery system effectively mitigated zoledronate-related osteonecrosis of the jaw and alleviated bone loss in experimental periodontitis.

Conclusions:

  • BRD9 plays a significant role in regulating osteoclastogenesis and bone resorption.
  • Targeting BRD9 presents a promising therapeutic avenue for various bone diseases, including osteonecrosis of the jaw and aggressive periodontitis.

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