title: NF-κB RELA-deficient bone marrow macrophages fail to support bone formation and to maintain the hematopoietic niche after lethal irradiation and stem cell transplantation.
abstract: Bone remodeling and hematopoiesis are interrelated and bone marrow (BM) macrophages are considered to be important for both bone remodeling and maintenance of the hematopoietic niche. We found that NF-κB Rela-deficient chimeric mice, generated by transplanting Rela (-/-) fetal liver cells into lethally irradiated hosts, developed severe osteopenia, reduced lymphopoiesis and enhanced mobilization of hematopoietic stem and progenitor cells when BM cells were completely substituted by Rela-deficient cells. Rela (-/-) hematopoietic stem cells from fetal liver had normal hematopoietic ability, but those harvested from the BM of osteopenic Rela (-/-) chimeric mice had reduced repopulation ability, indicating impairment of the microenvironment for the hematopoietic niche. Osteopenia in Rela (-/-) chimeric mice was due to reduced bone formation, even though osteoblasts differentiated from host cells. This finding indicates impaired functional coupling between osteoblasts and hematopoietic stem cell-derived cells. Rela-deficient BM macrophages exhibited an aberrant inflammatory phenotype, and transplantation with wild-type F4/80(+) BM macrophages recovered bone formation and ameliorated lymphopoiesis in Rela (-/-) chimeric mice. Therefore, RELA in F4/80(+) macrophages is important both for bone homeostasis and for maintaining the hematopoietic niche after lethal irradiation and hematopoietic stem cell transplantation.
authors.affiliation: Technology and Development Team for BioSignal Program, RIKEN BioResource Center, RIKEN Institute, Tsukuba 305-074, Japan smise@brc.riken.jp.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Mise-Omata
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Peradeniya 20400, Sri Lanka.
authors.forename: Neil
authors.initials: N
authors.lastname: Alles
authors.affiliation: Technology and Development Team for BioSignal Program, RIKEN BioResource Center, RIKEN Institute, Tsukuba 305-074, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Fukazawa
authors.affiliation: Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohya
authors.affiliation: Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu 803-8580, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
authors.affiliation: Technology and Development Team for BioSignal Program, RIKEN BioResource Center, RIKEN Institute, Tsukuba 305-074, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Obata
authors.affiliation: Technology and Development Team for BioSignal Program, RIKEN BioResource Center, RIKEN Institute, Tsukuba 305-074, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D038041:Lymphopoiesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D055153:Stem Cell Niche / Q000235:genetics*; D051996:Transcription Factor RelA / Q000172:deficiency* / Q000235:genetics; D018183:Transplantation Chimera; D014916:Whole-Body Irradiation
chemical_list: D051996:Transcription Factor RelA
keywords: NF-κB; bone remodeling; hematopoietic niche; macrophage; osteoimmunology