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A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

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.

SUBMITTER: Jones KB

PROVIDER: S-EPMC2836675 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

Jones Kevin B KB Piombo Virginia V Searby Charles C Kurriger Gail G Yang Baoli B Grabellus Florian F Roughley Peter J PJ Morcuende Jose A JA Buckwalter Joseph A JA Capecchi Mario R MR Vortkamp Andrea A Sheffield Val C VC

Proceedings of the National Academy of Sciences of the United States of America 20091222 5

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 e ...[more]

PMID: 20080592

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Project description:NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell-1 in endochondral ossification by investigating Nell-1-specific inactivation in Col2α1-expressing cell lineages. Nell-1flox/flox ; Col2α1-Cre+ (Nell-1Col2α1 KO) mice were generated for comprehensive analysis. Nell-1Col2α1 KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell-1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell-1Col2α1 KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV/TV), trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro-CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col-2, Col-10, and fewer BrdU-positive chondrocytes were observed in thinner Nell-1Col2α1 KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched-1, PTHrP, and PTHrP receptor. Primary Nell-1Col2α1 KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh-PTHrP signaling molecules can be partially rescued by exogenous Nell-1 protein. Moreover, intranuclear Gli-1 protein and gene expression of the Gli-1 downstream target genes, Hip-1 and N-Myc, were also significantly decreased with Nell-1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell-1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte-specific Nell-1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh-PTHrP feedback loop. © 2018 American Society for Bone and Mineral Research.

Dataset Information

A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

Publications

A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

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