Kevin B Jones, Virginia Piombo, Charles Searby+9 more · 2010 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
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 cartil Show more
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. Show less
The osteochondroma is a common, benign, primary tumor of bone. A mechanism for its pathogenesis has not been identified, but loss of function of EXT genes is implicated in sporadic and hereditary mult Show more
The osteochondroma is a common, benign, primary tumor of bone. A mechanism for its pathogenesis has not been identified, but loss of function of EXT genes is implicated in sporadic and hereditary multiple osteochondromas. Recent advances in the understanding of other molecular signaling pathways in the physis cast doubt on the latest pathogenetic theories. These advances are reviewed and used as the basis for a revised theory for pathogenesis: A clone of proliferating chondrocytes without functional EXT1 (or EXT2) expression fails to produce heparan sulfate; lack of heparan sulfate at the cell surface disrupts fibroblast growth factor signaling and Indian hedgehog diffusion, leading to focal overproliferation and adjacent bone collar deficiency, respectively; together these effects are proposed to contribute to osteochondroma pathogenesis. Show less