title: Transgenic expression of CSF-1 in CSF-1 receptor-expressing cells leads to macrophage activation, osteoporosis, and early death.
abstract: CSF-1 is the primary mononuclear phagocyte and osteoclast growth factor. Autocrine regulation by CSF-1 has been reported in macrophages during inflammatory responses and in neoplastic cells. To investigate whether inflammatory disease or neoplasia was the dominant consequence of autocrine regulation by CSF-1 in CSF-1 receptor (CSF-1R)-expressing cells, we created mice that express CSF-1 under the control of the CSF-1R promoter/first intron driver [transgene TgN(Csf1r-Csf1)Ers (TgRC) mice], which have reduced thymic size, a short lifetime, and low body weight and develop osteoporosis. In 4-week-old TgRC mice, osteoclast numbers are elevated, and macrophage densities are increased in bone marrow, spleen, liver, and brain. Cultured TgRC macrophages express CSF-1 and proliferate without exogenous CSF-1 and in the presence of neutralizing antimouse CSF-1 antibody. Compared with macrophages from nontransgenic littermates, TgRC macrophages exhibit a stellate morphology, express elevated mRNAs for proinflammatory cytokines, and despite a lower, steady-state cytokine secretion, secrete elevated levels of inflammatory cytokines in response to LPS, indicating that TgRC macrophages are functionally primed through the CSF-1R. Thus, autocrine regulation of CSF-1R-expressing cells by CSF-1 leads to a severe phenotype that emphasizes the importance of the known, local production of CSF-1 in inflammatory disease.
authors.affiliation: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Suwen
authors.initials: S
authors.lastname: Wei
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Dai
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010024:Osteoporosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology*; D019076:Transgenes / Q000276:immunology
chemical_list: D000906:Antibodies; D016207:Cytokines; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor