1. Loss of murine Gfi1 causes neutropenia and induces osteoporosis depending on the pathogen load and systemic inflammation
- Author
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Geissler, Sven, Textor, Martin, Stumpp, Sabine, Seitz, Sebastian, Lekaj, Anja, Brunk, Sabrina, Klaassen, Sabine, Schinke, Thorsten, Klein, Christoph, Mundlos, Stefan, Kornak, Uwe, and Kühnisch, Jirko
- Subjects
Male ,Neutrophils ,Physiology ,Organogenesis ,Osteoclasts ,lcsh:Medicine ,Pathology and Laboratory Medicine ,White Blood Cells ,Mice ,Animal Cells ,Osteogenesis ,Immune Physiology ,Medicine and Health Sciences ,Congenital Bone Marrow Failure Syndromes ,lcsh:Science ,Immune Response ,Connective Tissue Cells ,Mice, Knockout ,Innate Immune System ,Cell Differentiation ,DNA-Binding Proteins ,Connective Tissue ,Trichomonas ,Cytokines ,Anatomy ,Cellular Types ,Research Article ,Neutropenia ,Genotype ,Immune Cells ,Immunology ,Osteocytes ,Bone and Bones ,Signs and Symptoms ,Diagnostic Medicine ,Animals ,Bone ,Inflammation ,Osteoblasts ,Blood Cells ,Bone Development ,Body Weight ,RANK Ligand ,lcsh:R ,Osteoprotegerin ,Biology and Life Sciences ,Extremities ,Cell Biology ,Molecular Development ,Mice, Inbred C57BL ,Biological Tissue ,Cardiovascular and Metabolic Diseases ,Immune System ,Osteoporosis ,lcsh:Q ,Pasteurellaceae ,Organism Development ,Developmental Biology ,Transcription Factors - 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.
- Published
- 2018