title: Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects.
abstract: CSF-1, a key regulator of mononuclear phagocyte production, is highly expressed in the skeleton by osteoblasts/osteocytes and in a number of nonskeletal tissues such as uterus, kidney and brain. The spontaneous mutant op/op mouse has been the conventional model of CSF-1 deficiency and exhibits a pleiotropic phenotype characterized by osteopetrosis, and defects in hematopoiesis, fertility and neural function. Studies to further delineate the biologic effect of CSF-1 within various tissues have been hampered by the lack of suitable models. To address this issue, we generated CSF-1 floxed/floxed mice and demonstrate that Cre-mediated recombination using Meox2Cre, a Cre line expressed in epiblast during early embryogenesis, results in mice with ubiquitous CSF-1 deficiency (CSF-1KO). Homozygous CSF-1KO mice lacked CSF-1 in all tissues and displayed, in part, a similar phenotype to op/op mice that included: failure of tooth eruption, osteopetrosis, reduced macrophage densities in reproductive and other organs and altered hematopoiesis with decreased marrow cellularity, circulating monocytes and B cell lymphopoiesis. In contrast to op/op mice, CSF-1KO mice showed elevated circulating and splenic T cells. A striking feature in CSF-1KO mice was defective osteocyte maturation, bone mineralization and osteocyte-lacunar system that was associated with reduced dentin matrix protein 1 (DMP1) expression in osteocytes. CSF-1KO mice also showed a dramatic reduction in osteomacs along the endosteal surface that may have contributed to the hematopoietic and cortical bone defects. Thus, our findings show that ubiquitous CSF-1 gene deletion using a Cre-based system recapitulates the expected osteopetrotic phenotype. Moreover, results point to a novel link between CSF-1 and osteocyte survival/function that is essential for maintaining bone mass and strength during skeletal development.
authors.affiliation: Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Harris
authors.forename: Mary
authors.initials: M
authors.lastname: MacDougall
authors.forename: Diane
authors.initials: D
authors.lastname: Horn
authors.forename: Kathleen
authors.initials: K
authors.lastname: Woodruff
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Zimmer
authors.forename: Vivienne I
authors.initials: VI
authors.lastname: Rebel
authors.forename: Roberto
authors.initials: R
authors.lastname: Fajardo
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Jelica
authors.initials: J
authors.lastname: Gluhak-Heinrich
authors.forename: Marie A
authors.initials: MA
authors.lastname: Harris
authors.forename: Sherry
authors.initials: S
authors.lastname: Abboud Werner
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology / Q000502:physiology; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010011:Osteocytes / Q000166:cytology / Q000473:pathology*; D010022:Osteopetrosis / Q000473:pathology* / Q000503:physiopathology; D014070:Tooth / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D014078:Tooth Eruption / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D018398:Homeodomain Proteins; C484194:Meox2 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; C045073:Cre recombinase; D019426:Integrases