Journal article
Mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
Proceedings of the National Academy of Sciences - PNAS, Vol.107(5), pp.2054-2059
02/02/2010
DOI: 10.1073/pnas.0910875107
PMCID: PMC2836675
PMID: 20080592
Abstract
We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. Mice heterozygous for Ext1 or Ext2, modeling the human genotypes that cause MO, occasionally develop solitary osteochondroma-like structures on ribs [Lin et al. (2000) Dev Biol 224(2):299-311; Stickens et al. (2005) Development 132(22):5055-5068]. Rather than model the germ-line genotype, we modeled the chimeric tissue genotype of somatic loss of heterozygosity (LOH), by conditionally inactivating Ext1 via head-to-head loxP sites and temporally controlled Cre-recombinase in chondrocytes. These mice faithfully recapitulate the human phenotype of multiple metaphyseal osteochondromas. We also confirm homozygous disruption of Ext1 in osteochondroma chondrocytes and their origin in proliferating physeal chondrocytes. These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type.
Details
- Title: Subtitle
- Mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
- Creators
- Kevin B JonesVirginia PiomboCharles Searby - University of Iowa, Stead Family Department of PediatricsGail KurrigerBaoli Yang - University of Iowa, BioVentures CenterFlorian GrabellusPeter J RoughleyJose A Morcuende - University of Iowa, Orthopedics and RehabilitationJoseph A Buckwalter - University of Iowa, Orthopedics and RehabilitationMario R CapecchiAndrea VortkampVal C Sheffield - University of Iowa, Stead Family Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.107(5), pp.2054-2059
- DOI
- 10.1073/pnas.0910875107
- PMID
- 20080592
- PMCID
- PMC2836675
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- Orthopedic Research and Education Foundation Howard Hughes Medical Institute National Institutes of Health: EY-11298, EY-17168, 5R37HD030701-16 Deutsche Forschungsgemeinschaft: VO 620/9-1
We thank Henry M. Kronenberg (Massachusetts General Hospital) for providing the Osx-CreERT mouse, Oliver Smithies (University of North Carolina at Chapel Hill) for pOSDUPDEL, and Matt F. Hockin (University of Utah) for the TATCre protein. This work was supported by the Orthopedic Research and Education Foundation 2003 Centerpulse Resident Grant for Growth Factor Research; by the Howard Hughes Medical Institute; by National Institutes of Health Grants EY-11298, EY-17168, and 5R37HD030701-16; and by Grant VO 620/9-1 from the Deutsche Forschungsgemeinschaft (to A. V.).
- Language
- English
- Date published
- 02/02/2010
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Orthopedics and Rehabilitation; Medical Genetics and Genomics; BioVentures Center; Obstetrics and Gynecology; Ophthalmology and Visual Sciences
- Record Identifier
- 9983557774902771
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