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

Geissler, Sven; Textor, Martin; Stumpp, Sabine; Seitz, Sebastian; Lekaj, Anja; Brunk, Sabrina; Klaassen, Sabine; Schinke, Thorsten; Klein, Christoph; Mundlos, Stefan; Kornak, Uwe; Kühnisch, Jirko

doi:10.1371/journal.pone.0198510

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

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Mundlos, Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany;
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany;

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Kornak, Uwe
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany;
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany;

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Citation

Geissler, S., Textor, M., Stumpp, S., Seitz, S., Lekaj, A., Brunk, S., et al. (2018). Loss of murine Gfi1 causes neutropenia and induces osteoporosis depending on the pathogen load and systemic inflammation. PLoS One, 13(6): e0198510. doi:10.1371/journal.pone.0198510.

Cite as: https://hdl.handle.net/21.11116/0000-0003-5C75-3

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.