Loss of murine Gfi1 causes neutropenia and induces osteoporosis depending on the pathogen load and systemic inflammation

PLoS One. 2018 Jun 7;13(6):e0198510. doi: 10.1371/journal.pone.0198510. eCollection 2018.

Abstract

Gfi1 is a key molecule in hematopoietic lineage development and mutations in GFI1 cause severe congenital neutropenia (SCN). Neutropenia is associated with low bone mass, but the underlying mechanisms are poorly characterized. Using Gfi1 knock-out mice (Gfi1-ko/ko) as SCN model, we studied the relationship between neutropenia and bone mass upon different pathogen load conditions. Our analysis reveals that Gfi1-ko/ko mice kept under strict specific pathogen free (SPF) conditions demonstrate normal bone mass and survival. However, Gfi1-ko/ko mice with early (nonSPF) or late (SPF+nonSPF) pathogen exposure develop low bone mass. Gfi1-ko/ko mice demonstrate a striking rise of systemic inflammatory markers according to elevated pathogen exposure and reduced bone mass. Elevated inflammatory cytokines include for instance Il-1b, Il-6, and Tnf-alpha that regulate osteoclast development. We conclude that low bone mass, due to low neutrophil counts, is caused by the degree of systemic inflammation promoting osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / physiology
  • Cell Differentiation
  • Congenital Bone Marrow Failure Syndromes
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Extremities / pathology
  • Genotype
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutropenia / congenital*
  • Neutropenia / etiology
  • Neutropenia / genetics
  • Neutropenia / pathology
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteogenesis
  • Osteoporosis / etiology*
  • Osteoporosis / genetics
  • Osteoporosis / pathology
  • Osteoprotegerin / blood
  • Pasteurellaceae / pathogenicity
  • RANK Ligand / blood
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Trichomonas / pathogenicity

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Gfi1 protein, mouse
  • Osteoprotegerin
  • RANK Ligand
  • Transcription Factors

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3

Grants and funding

SM and UK received a Deutsche Forschungsgemeinschaft (DFG) Schwerpunktprogramm SPP 1468 Immunobone research grant. JK, SaS, and AL were supported by the SPP 1468 Immunobone. SG and MT were partially supported by the BMBF (DIMEOS, 01EC1402B) and the DFG Research Unit (FOR 2165; grant GE2512/2-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.