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 the 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.

Porous poly (D,L‐lactide‐co‐glycolide) acid/biosilicate® composite scaffolds for bone tissue engineering

“…Also, BMPs induce the expression of osteogenic transcription factor, such as Runx2, ALP, and OC . Runx2, a member of the Runt‐related family of transcription factors is essential to osteoblast differentiation and regulation of the expression of many extracellular matrix proteins during bone cell differentiation . Runx2 acts mainly in the early stages of endochondral bone formation .…”

Variance of spinal osteoporosis induced by dexamethasone and methylprednisolone and its associated mechanism

“…RUNX2, as a major osteoblastic transcription factor in mammalian bone, is essential for proper skeletal morphogenesis and bone stabilization due to that it contributes to both intramembranous and endochondral bone formation processes [46]. Therefore, germline deletion of Runx2 is lethal because it prevents formation of amature, mineralized skeleton [47,48], which may explain the conclusion that dexamethasone causes more serious spinal osteoporosis than does methylprednisolone.…”

Evidence for Altered Canonical Wnt Signaling in the Trabecular Bone of Elderly Postmenopausal Women with Fragility Femoral Fracture

“…Our study found that the F cohort, compared to OA, shows downregulated expression of RUNX2, a key transcription factor [25] that determines osteoblastic differentiation from mesenchymal precursors and is therefore required for the early stages of endochondral bone formation [26]. Low expression of RUNX2 might affect the downstream processes of osteoblast maturation [27]; thus, RUNX2 regulation might be critical in tipping the balance of bone remodeling away from equilibrium, with the result of bone fragility.…”