TY - JOUR
T1 - Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects
AU - Harris, Stephen E.
AU - MacDougall, Mary
AU - Horn, Diane
AU - Woodruff, Kathleen
AU - Zimmer, Stephanie N.
AU - Rebel, Vivienne I.
AU - Fajardo, Roberto
AU - Feng, Jian Q.
AU - Gluhak-Heinrich, Jelica
AU - Harris, Marie A.
AU - Abboud Werner, Sherry
N1 - Funding Information:
This work has been supported, in part, by funding from the National Institutes of Health ( R01 AR042306 , Veteran's Administration Merit grant, S.A-W), National Institute of Health ( P01 AR46798 , S.E.H. and J.Q.F.) and with funding from the GCCRI/UTHSCSA (VIR). We thank the micro-CT Core Facility at UTHSCSA for their assistance in analyzing the skeletal tissues.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Colony stimulating factor-1 (CSF-1)
KW - Dentin matrix protein 1 (DMP1)
KW - Knockout mouse
KW - Osteoblasts
KW - Osteocytes
UR - http://www.scopus.com/inward/record.url?scp=80053911477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053911477&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2011.09.038
DO - 10.1016/j.bone.2011.09.038
M3 - Article
C2 - 21958845
AN - SCOPUS:80053911477
SN - 8756-3282
VL - 50
SP - 42
EP - 53
JO - Bone
JF - Bone
IS - 1
ER -