Integration of Multiple Signaling Pathways Determines Differences in the Osteogenic Potential and Tissue Regeneration of Neural Crest-Derived and Mesoderm-Derived Calvarial Bones

Abstract

The mammalian skull vault, a product of a unique and tightly regulated evolutionary process, in which components of disparate embryonic origin are integrated, is an elegant model with which to study osteoblast biology. Our laboratory has demonstrated that this distinct embryonic origin of frontal and parietal bones confer differences in embryonic and postnatal osteogenic potential and skeletal regenerative capacity, with frontal neural crest derived osteoblasts benefitting from greater osteogenic potential. We outline how this model has been used to elucidate some of the molecular mechanisms which underlie these differences and place these findings into the context of our current understanding of the key, highly conserved, pathways which govern the osteoblast lineage including FGF, BMP, Wnt and TGFβ signaling. Furthermore, we explore recent studies which have provided a tantalizing insight into way these pathways interact, with evidence accumulating for certain transcription factors, such as Runx2, acting as a nexus for cross-talk.

Neural crest cell signaling pathways critical to cranial bone development and pathology

“…Both CNCC derived and paraxial mesoderm derived osteoprogenitor cells undergo intramembranous ossification to generate corresponding skull elements; however, they show some differences in osteogenic potential and skeletal regenerative capacity [26]. Osteoblasts from neural crest-derived bones such as the frontal bone feature a higher level of activation of FGF signaling pathways compared with osteoblasts from paraxial mesoderm-derived bones such as parietal bones [27, 28].…”

Small Molecule Inhibition of Transforming Growth Factor Beta Signaling Enables the Endogenous Regenerative Potential of the Mammalian Calvarium

“…8,9 We have previously showed that the disparate embryonic tissue origin of mammalian calvarium 10 leads to significant differences in the activity of key signaling pathways that govern osteogenic and regenerative potential. [11][12][13][14][15] Recently, we have identified that enhanced transforming growth factor beta (TGFb) signaling in mesoderm-derived parietal bone osteoblasts (PObs) has a key role in determining their elevated apoptotic activity and diminished osteogenic capacity. 16 This finding provides the impetus for our current study, which investigates the possibility of potentiating bone regeneration in the mammalian calvarium through inhibition of TGFb signaling by employing the small molecule SB431542.…”

Physiological Signatures of Dual Embryonic Origins in Mouse Skull Vault

“…Enhanced activation of Wnt signaling is capable to transform the physiological behavior of parietal bone into a degree similar to neural crest derived frontal bone [6]. Besides, frontal bone tissues show low apoptosis when stimulated by TGF signaling [7]. Due to superior activities of osteoblasts and bone regeneration within frontal bone, a novel thought for craniofacial construction–endogenous calvarial regeneration has been proposed.…”