SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion. Academic Article uri icon

Overview

abstract

  • Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

publication date

  • August 27, 2024

Research

keywords

  • Cell Differentiation
  • Interferon Regulatory Factor-7
  • Osteoclasts
  • Sterol Regulatory Element Binding Protein 2

Identity

PubMed Central ID

  • PMC11350122

Scopus Document Identifier

  • 85202148053

Digital Object Identifier (DOI)

  • 10.1038/s41413-024-00354-4

PubMed ID

  • 39191742

Additional Document Info

volume

  • 12

issue

  • 1