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.
Highlights
NDRG1 has been implicated in lipid synthesis and myelination[8]
NDRG1 is required for the proliferation and differentiation of both BM-derived macrophages (BMDMs) and BMDCs when stimulated with macrophage colony-stimulating factor (M-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF), respectively
This study provides the first demonstration that NDRG1 is required for the differentiation of macrophage lineage cells, supporting bone remodeling and pathological angiogenesis (Fig. 7)
Summary
NDRG1 has been implicated in lipid synthesis and myelination[8]. Ndrg[1] knockout (KO) mice retain complex motor skills but exhibit muscle weakness, the progressive demyelination of nerves[9] and Schwann cell www.nature.com/scientificreports/. Ndrg[1] KO mice exhibit a decreased number of mast cells that display impaired degranulation, indicating an attenuated immune response to antigens[13]. Together, these data indicate that NDRG1 may modulate various differentiation processes in the nervous and immune systems. Macrophages are known to play crucial roles in the growth, angiogenesis and metastasis of cancer cells[19,20]. It remains unclear whether NDRG1 can modulate tumor progression by acting on progenitor cells, including macrophages. The possible role of NDRG1 in these processes was discussed in the context of the differentiation and activation of macrophage lineage cells
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