Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice

Meghan E. McGee-Lawrence, Lomeli R. Carpio, Elizabeth W. Bradley, Amel Dudakovic, Jane B. Lian, Andre J. van Wijnen, Sanjeev Kakar, Wei Hsu, Jennifer J. Westendorf

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38 Scopus citations


Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/- mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/- mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in Axin2-/-:Runx2+/- mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/- mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2-/-:Runx2+/- calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/- and double mutant Axin2-/-:Runx2+/- mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/- mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2-/- mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation.

Original languageEnglish (US)
Pages (from-to)277-286
Number of pages10
StatePublished - Sep 2014

Bibliographical note

Funding Information:
The NIH ( R01 DE020194 , R37 DE012528 , T32 AR056950 , F32 AR60140 , F32 AR061873 ) and the Mayo Clinic Center for Regenerative Medicine supported this work. MEML, EWB, LRC, AD, SK and JJW contributed to the study design, data acquisition and analysis, and manuscript drafting. MEML, JBL, AJvW, WH, and JJW contributed to the interpretation of data and critical review of the manuscript. MEML and JJW are accountable for the accuracy and integrity of the work. The authors thank Dr. David Razidlo, Xiaodong Li, Bridget Stensgard, and Jim Herrick for the technical assistance with animals and histology. The authors also thank the Mayo Clinic Medical Genome Facility Gene Expression Core and Dr. Ying Li from the Mayo Clinic Biomedical Statistics & Informatics Division of Health Sciences Research for microarray data collection and analysis.


  • Axin2
  • Cleidocranial dysplasia
  • Endochondral bone formation
  • Runx2
  • Wnt signaling


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