PMID- 29879182 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20191210 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 6 DP - 2018 TI - Loss of murine Gfi1 causes neutropenia and induces osteoporosis depending on the pathogen load and systemic inflammation. PG - e0198510 LID - 10.1371/journal.pone.0198510 [doi] LID - e0198510 AB - 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. FAU - Geissler, Sven AU - Geissler S AUID- ORCID: 0000-0002-8750-6324 AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Julius Wolff Institute, Berlin, Germany. FAU - Textor, Martin AU - Textor M AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Julius Wolff Institute, Berlin, Germany. FAU - Stumpp, Sabine AU - Stumpp S AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany. FAU - Seitz, Sebastian AU - Seitz S AD - University Medical Center Hamburg-Eppendorf, Department of Orthopaedics, Hamburg, Germany. FAU - Lekaj, Anja AU - Lekaj A AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany. FAU - Brunk, Sabrina AU - Brunk S AD - Institut fur Tierpathologie, Berlin, Germany. FAU - Klaassen, Sabine AU - Klaassen S AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charite Medical Faculty and the Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Department of Pediatric Cardiology, Berlin, Germany. FAU - Schinke, Thorsten AU - Schinke T AD - University Medical Center Hamburg-Eppendorf, Department of Osteology and Biomechanics, Hamburg, Germany. FAU - Klein, Christoph AU - Klein C AD - Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Department of Pediatrics, Munich, Germany. FAU - Mundlos, Stefan AU - Mundlos S AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany. AD - Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany. FAU - Kornak, Uwe AU - Kornak U AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany. AD - Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany. FAU - Kuhnisch, Jirko AU - Kuhnisch J AUID- ORCID: 0000-0003-4744-5421 AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Institute for Medical Genetics and Human Genetics, Berlin, Germany. AD - Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charite Medical Faculty and the Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. AD - Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180607 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Cytokines) RN - 0 (DNA-Binding Proteins) RN - 0 (Gfi1 protein, mouse) RN - 0 (Osteoprotegerin) RN - 0 (RANK Ligand) RN - 0 (Transcription Factors) RN - Neutropenia, Severe Congenital, Autosomal Recessive 3 SB - IM MH - Animals MH - Body Weight MH - Bone and Bones/diagnostic imaging/physiology MH - Cell Differentiation MH - Congenital Bone Marrow Failure Syndromes MH - Cytokines/genetics/metabolism MH - DNA-Binding Proteins/deficiency/*genetics MH - Extremities/pathology MH - Genotype MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neutropenia/*congenital/etiology/genetics/pathology MH - Osteoblasts/cytology/metabolism MH - Osteogenesis MH - Osteoporosis/*etiology/genetics/pathology MH - Osteoprotegerin/blood MH - Pasteurellaceae/pathogenicity MH - RANK Ligand/blood MH - Transcription Factors/deficiency/*genetics MH - Trichomonas/pathogenicity PMC - PMC5991660 COIS- The authors have declared that no competing interests exist. EDAT- 2018/06/08 06:00 MHDA- 2018/12/12 06:00 PMCR- 2018/06/07 CRDT- 2018/06/08 06:00 PHST- 2018/01/18 00:00 [received] PHST- 2018/05/21 00:00 [accepted] PHST- 2018/06/08 06:00 [entrez] PHST- 2018/06/08 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/06/07 00:00 [pmc-release] AID - PONE-D-18-01831 [pii] AID - 10.1371/journal.pone.0198510 [doi] PST - epublish SO - PLoS One. 2018 Jun 7;13(6):e0198510. doi: 10.1371/journal.pone.0198510. eCollection 2018.