title: Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice.
abstract: 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.
authors: Mayo Clinic, Rochester, MN, USA.
authors: Meghan E
authors: ME
authors: McGee-Lawrence
authors: Mayo Clinic, Rochester, MN, USA.
authors: Lomeli R
authors: LR
authors: Carpio
authors: Mayo Clinic, Rochester, MN, USA.
authors: Elizabeth W
authors: EW
authors: Bradley
authors: Mayo Clinic, Rochester, MN, USA.
authors: Amel
authors: A
authors: Dudakovic
authors: University of Vermont, Burlington, VT, USA.
authors: Jane B
authors: JB
authors: Lian
authors: Mayo Clinic, Rochester, MN, USA.
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Mayo Clinic, Rochester, MN, USA.
authors: Sanjeev
authors: S
authors: Kakar
authors: University of Rochester Medical Center, Rochester, NY, USA.
authors: Wei
authors: W
authors: Hsu
authors: Mayo Clinic, Rochester, MN, USA. Electronic address: westendorf.jennifer@mayo.edu.
authors: Jennifer J
authors: JJ
authors: Westendorf
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000172:deficiency* / Q000378:metabolism; D002356:Cartilage / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis / Q000235:genetics; D002973:Cleidocranial Dysplasia / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D055762:Cranial Fontanelles / Q000000981:diagnostic imaging / Q000473:pathology; D018450:Disease Progression; D017102:Fracture Healing; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000235:genetics; D009929:Organ Size; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D012886:Skull / Q000473:pathology*; D014945:Wound Healing; D055114:X-Ray Microtomography
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse
keywords: Axin2; Cleidocranial dysplasia; Endochondral bone formation; Runx2; Wnt signaling