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.
Highlights
Neutrophils are the predominant innate immune cell subtype that mediates initial response to infection [1]
Previous reports demonstrate an association of low neutrophil counts with chronic inflammation and osteopenia in neutropenic patients [9, 10] the underlying mechanisms have been insufficiently characterized
We utilize Gfi1 knock-out mice as a model for Severe congenital neutropenia (SCN) to assess the mechanism leading to low bone mass
Summary
Neutrophils are the predominant innate immune cell subtype that mediates initial response to infection [1]. Via chemoattractive cues neutrophils are recruited from the circulation to sites of infection and attack bacterial or fungal pathogens with an arsenal of potent antimicrobial mechanisms. These mechanisms include the release of cytotoxic molecules via degranulation of intracellular vesicles, phagocytosis, generation of neutrophil extracellular traps, production of reactive oxygen species, and synthesis of prostaglandins/leucotrienes [1, 2]. Familial forms of SCN or CN are caused by mutations within the neutrophil elastase (ELANE), growth factor independence 1 transcription repressor (GFI1), HCLS1-associated protein X-1 (HAX1), glucose-6-phosphatase 3 (G6PC3), Wiskott-Aldrich syndrome protein (WAS), and vacuolar protein sorting 45 homolog (VPS45) genes [5]. A largely uncharacterized aspect of low neutrophil counts is osteopenia and osteoporosis [6,7,8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
