Twist1-Haploinsufficiency Selectively Enhances the Osteoskeletal Capacity of Mesoderm-Derived Parietal Bone Through Downregulation of Fgf23

Abstract

Craniofacial development is a program exquisitely orchestrated by tissue contributions and regulation of genes expression. The basic helix–loop–helix (bHLH) transcription factor Twist1 expressed in the skeletal mesenchyme is a key regulator of craniofacial development playing an important role during osteoskeletogenesis. This study investigates the postnatal impact of Twist1 haploinsufficiency on the osteoskeletal ability and regeneration on two calvarial bones arising from tissues of different embryonic origin: the neural crest-derived frontal and the mesoderm-derived parietal bones. We show that Twist1 haplonsufficiency as well Twist1-sh-mediated silencing selectively enhanced osteogenic and tissue regeneration ability of mesoderm-derived bones. Transcriptomic profiling, gain-and loss-of-function experiments revealed that Twist1 haplonsufficiency triggers its selective activity on mesoderm-derived bone through a sharp downregulation of the bone-derived hormone Fgf23 that is upregulated exclusively in wild-type parietal bone.

Regional difference in microRNA regulation in the skull vault

“…The higher rich factor indicated higher enrichment regeneration compared to mesoderm derived parietal bone. 4,8,10,11 In our study, we further revealed another feature in the frontal and parietal bone with a distinct miRNA pattern.…”

“…Since the establishment of dual tissue origins in the frontal bones and parietal bones, neural crest‐derived frontal bone have been found with superior osteogenic capacities for bone regeneration compared to mesoderm derived parietal bone . In our study, we further revealed another feature in the frontal and parietal bone with a distinct miRNA pattern.…”

“…1,2 Interestedly, frontal bone-derived osteoblasts are found less differentiated, faster growing, and faster bone nodule forming compared to parietal bone-derived osteoblasts in vitro. 3 Besides, frontal bone osteoblasts exhibited superior osteogenic capacities, [3][4][5][6][7][8][9][10][11][12] displaying superior abilities for bone regeneration to heal damaged bone in vivo. Therefore, the skull vault is a suitable model to study osteogenic potential, and the identifications of proper targets to manipulate osteogenic potential will be valuable to treat bone defects in the clinic.…”

BMP Signaling in the Development and Regeneration of Cranium Bones and Maintenance of Calvarial Stem Cells

“…Ideally, a suitable cytokine or drug would be sufficient to initiate the endogenous program for bone healing. FGF and Wnt signaling are able to quicken bone healing from injury (Xu et al, 2007;Quarto et al, 2009Quarto et al, , 2010Quarto et al, , 2018Behr et al, 2010;Ichikawa et al, 2015;Li et al, 2015;Hu et al, 2017;Wu et al, 2017;Doro et al, 2019). BMPs, receptors, and intracellular Smads have robust expressions in the periosteum after a fracture, and their expressions are detectable in endothelial cells that associated with new bone formation (Yu et al, 2010).…”

“…The calvaria provides important protection for the growth and formation of the brain, and its growth is concordantly orchestrated across developmental stages. Since the establishment of the dual-tissue lineages of the calvaria (Jiang et al, 2002), studies are focusing on region-dependent differential regulation of calvarial bone development (Quarto et al, 2009(Quarto et al, , 2010(Quarto et al, , 2018Wiren et al, 2011;Ichikawa et al, 2015;Li et al, 2015;Doro et al, 2019). On one hand, the region-dependent roles of evolutionally conserved signaling pathways in calvarial bones are under clarifying (Quarto et al, 2009;Behr et al, 2010;Li et al, 2010;Li et al, 2015).…”