Abstract
Bone formation and skeletal repair are dynamic processes involving a fine-tuned balance between osteoblast proliferation and differentiation orchestrated by multiple signaling pathways. Canonical Wnt (cWnt) signaling is known to playing a key role in these processes. In the current study, using a transgenic mouse model with targeted disruption of axin2, a negative regulator of cWnt signaling, we investigated the impact of enhanced activation of cWnt signaling on the osteogenic capacity and skeletal repair. Specifically, we looked at two calvarial bones of different embryonic tissue origin: the neural crest-derived frontal bone and the mesoderm-derived parietal bone, and we investigated the proliferation and apoptotic activity of frontal and parietal bones and derived osteoblasts. We found dramatic differences in cell proliferation and apoptotic activity between Axin2 -/- and wild type calvarial bones, with Axin2 -/- showing increased proliferative activity and reduced levels of apoptosis. Furthermore, we compared osteoblast differentiation and bone regeneration in Axin2 -/- and wild type neural crest-derived frontal and mesoderm-derived parietal bones, respectively. Our results demonstrate a significant increase either in osteoblast differentiation or bone regeneration in Axin2 -/- mice as compared to wild type, with Axin2 -/- parietal bone and derived osteoblasts displaying a “neural crest-derived frontal bone-like” profile, which is typically characterized by higher osteogenic capacity and skeletal repair than parietal bone. Taken together, our results strongly suggest that enhanced activation of cWnt signaling increases the skeletal potential of a calvarial bone of mesoderm origin, such as the parietial bone to a degree similar to that of a neural crest origin bone, like the frontal bone. Thus, providing further evidence for the central role played by the cWnt signaling in osteogenesis and skeletal-bone regeneration.
Highlights
Large defects in cranial or facial bones represent a major challenge in reconstructive surgery [1, 2]
Enhanced activation of Canonical Wnt (cWnt) signaling in Axin2-/- frontal bone and osteoblast cells (FOb) and parietal osteoblasts (POb) was confirmed by significantly up regulation of the target genes of cWnt signaling Cyclin D1 and c-Myc, as well by intense nuclear staining for active β-catenin in Axin2-/- POb cells as compared to wild type POb (Fig 1A and 1B)
We assessed the osteogenic capacity of FOb and POb isolated from neural crest-derived frontal bone and mesoderm-derived bone of postnatal day 21 (pN21) Axin2-/- and wild type mice, respectively
Summary
Large defects in cranial or facial bones represent a major challenge in reconstructive surgery [1, 2]. Children less than 2 years of age are capable of healing large calvarial defects, whereas adults lack this endogenous ability[3] Calvarial healing and underlying mechanism(s) have been widely studied both in vivo and in vitro [4,5,6,7,8,9]. In vitro and in vivo, enhanced activation of endogenous FGF, BMP and cWnt signaling pathways in the neural crest-derived frontal bone compared to the mesodermderived parietal bone. The latter bone displayed only increased activation of endogenous TGF-β signaling [9, 17]
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