title: Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice.
abstract: N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot-Marie-Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages.
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nabeshima
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Shinoda
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Fukunaga
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Karasuyama
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Fukushi
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume 830-8543, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016723:Bone Remodeling / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000172:deficiency*; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein