Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects
Open accessAbstract
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.
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HMGB1 and M-CSF have been suggested to be produced by osteocytes that stimulate osteoclast recruitment during bone remodeling.
“High mobility group box protein 1 (HMGB1) [198–200] and M-CSF [201] have also been suggested to be produced by osteocytes that stimulate osteoclast recruitment during bone remodeling [72, 73].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [201]
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- Authors
- Harris, S. E., MacDougall, M., Horn, D., Woodruff, K., Zimmer, S. N., Rebel, V. I., Fajardo, R., Feng, J. Q., Gluhak-Heinrich, J., Harris, M. A., & Abboud Werner, S.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Alabama at Birmingham (US)
- Venue
- Bone
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 50
- Issue
- 1
- Pages
- 42-53
- ISSN
- 1873-2763 (ISSN-L)
- 8756-3282
- PMC
- PMC3374485
- OpenAlex
- W2053766049
- Cited by
- 116
- References
- 50
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 7 · 2023: 14 · 2022: 5 · 2021: 15 · 2020: 13 · 2019: 9 · 2018: 10 · 2017: 3 · 2016: 7 · 2015: 7 · 2014: 3 · 2013: 2 · 2012: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Bone (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 AR042306, P01 AR46798)
- University of Texas Health Science Center at San Antonio
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- CSF-1, osteopetrosis, osteocytes, DMP1, bone mineralization, hematopoiesis, macrophages, monocytes, B cell lymphopoiesis, T cells, tooth eruption, skeletal development, bone mass
- MeSH terms
- Animals, Bone and Bones, Macrophages, Mice, Inbred C57BL, Mice, Mutant Strains, Osteocytes, Osteopetrosis, Tooth, Tooth Eruption, Macrophage Colony-Stimulating Factor, Mice, Knockout, Gene Targeting, Homeodomain Proteins, Integrases, Mice, X-Ray Microtomography
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