Deficiency of lipin2 results in enhanced nf‐κb signaling and osteoclast formation in raw‐d murine macrophages

Asami Watahiki, Seira Hoshikawa, Mitsuki Chiba, Hiroshi Egusa, Satoshi Fukumoto, Hiroyuki Inuzuka

Research output: Contribution to journalArticlepeer-review

Abstract

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)‐induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti‐inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF‐κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL‐mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine‐tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.

Original languageEnglish
Article number2893
Pages (from-to)1-14
Number of pages14
JournalInternational journal of molecular sciences
Volume22
Issue number6
DOIs
Publication statusPublished - 2021 Mar 2

Keywords

  • Autoinflammatory bone disorder
  • Inflammation
  • Lipin2
  • Macrophage
  • Majeed syndrome
  • Osteoclastogenesis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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