Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing

Authors

  • Do Y Soung,

    Corresponding author
    1. Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT, USA
    • University of Connecticut Health Center, Department of Orthopaedic Surgery, 263 Farmington Avenue, Farmington, CT 06034, USA.
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  • Laleh Talebian,

    1. Department of Biochemistry, Dartmouth Medical School, Hanover NH, USA
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  • Christina J Matheny,

    1. Department of Biochemistry, Dartmouth Medical School, Hanover NH, USA
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  • Rosa Guzzo,

    1. Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT, USA
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  • Maren E Speck,

    1. Department of Biochemistry, Dartmouth Medical School, Hanover NH, USA
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  • Jay R Lieberman,

    1. Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT, USA
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  • Nancy A Speck,

    1. Department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Biochemistry, Dartmouth Medical School, Hanover NH, USA
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  • Hicham Drissi

    Corresponding author
    1. Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT, USA
    2. Department of Genetics, University of Connecticut Health Center, Farmington, CT, USA
    • University of Connecticut Health Center, Department of Orthopaedic Surgery, 263 Farmington Avenue, Farmington, CT 06034, USA.
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Abstract

Runx1 is expressed in skeletal elements, but its role in fracture repair has not been analyzed. We created mice with a hypomorphic Runx1 allele (Runx1L148A) and generated Runx1L148A/− mice in which >50% of Runx1 activity was abrogated. Runx1L148A/− mice were viable but runted. Their growth plates had extended proliferating and hypertrophic zones, and the percentages of Sox9-, Runx2-, and Runx3-positive cells were decreased. Femoral fracture experiments revealed delayed cartilaginous callus formation, and the expression of chondrogenic markers was decreased. Conditional ablation of Runx1 in the mesenchymal progenitor cells of the limb with Prx1-Cre conferred no obvious limb phenotype; however, cartilaginous callus formation was delayed following fracture. Embryonic limb bud–derived mesenchymal cells showed delayed chondrogenesis when the Runx1 allele was deleted ex vivo with adenoviral-expressed Cre. Collectively, our data suggest that Runx1 is required for commitment and differentiation of chondroprogenitor cells into the chondrogenic lineage. © 2012 American Society for Bone and Mineral Research.

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