We put forward that the unique embryological origins of individual mammalian calvaria impact differences in their osteogenic capacity. The cental hypothesis of this proposal is that differences in embryonic origins of calvarial osteoblasts affect their embryonic and post-natal osteogenic potential and skeletal regenerative capacity. The paired parietal frontal bones in the anterior skull are derived from the neural crest and the paired parietal bones, positioned posteriorly, are derived from the paraxial mesoderm. We have preliminarily observed the frontal bone to possess superior osteogenic potential both in vitro and in vivo compared to the parietal bone. Our proposal aims to verify this difference in osteogenic potential and elucidate the role of fibroblast growth factor (FGF) signaling underlying this disparity. Such an understanding is of central importance to overcoming current challenges with treatment of calvarial defects. The inability of humans older than one year of age to reossify calvarial defects poses a substantial burden on our healthcare system. Current use of autogenous grafts, allogeneic substances, and synthetic materials to reconstruct calvarial defects are all suboptimal. These inadequacies serve as the impetus for our application. Through the identification of calvarial bones with inherently superior osteogenic capacity, we seek to gain insight into novel strategies for robust calvarial regeneration.
In Specific Aim 1, we will determine the role of FGF signaling in mediating differences between neural crest-derived frontal and paraxial mesoderm-derived parietal bone osteoblasts. Will begin by comparing the expression profile of key FGF ligands and receptors, and the activation of their downstream mediators, between the frontal and parietal bones of the wild-type and transgenic mice described above.
In Specific Aim 2, we will determine if the reduced healing capacity of paraxial mesoderm-derived parietal bone is augmented by the addition of exogenous FGF-2, -9, and -18 after injury in wild-type mice.
In Specific Aim 3, we will determine if the robust healing capacity of neural crest-derived frontal bone is reduced or negated in transgenic mice possessing fgf-2-/-, -9-/-, and -18-/- loss of function mutations. Ultimately, the translational goal of this application is to identify key molecular mechanisms in the FGF family that promote robust bone regeneration. We assert that the identification of calvarial bones with superior osteogenic capacity will provide insight into such mechanisms.

Public Health Relevance

The individual bones of the skull originate from different parts of the embryo. Our application aims to investigate whether this dissimilarity in origin translates into differences in their ability to heal skull defects. Furthermore, our application aims to elucidate the mechanisms underlying superior bone healing. This is of direct relevance to improving current treatment modalities for reconstructing skull defects. Defects in the skull represent a substantial biomedical burden on the US healthcare system. A myriad of reconstructive options are currently employed, each with their inherent inadequacies. Identification of skull bones with superior healing potential provides insight into novel strategies that can be employed to regenerate, rather than reconstruct, skull bones.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Senarath-Yapa, Kshemendra; McArdle, Adrian; Renda, Andrea et al. (2014) Adipose-derived stem cells: a review of signaling networks governing cell fate and regenerative potential in the context of craniofacial and long bone skeletal repair. Int J Mol Sci 15:9314-30
Tevlin, Ruth; McArdle, Adrian; Chan, Charles K F et al. (2014) Osteoclast derivation from mouse bone marrow. J Vis Exp :e52056
Lo, David D; McArdle, Adrian; Senarath-Yapa, Kshemendra et al. (2013) Commentary on the differential healing capacity of calvarial bone. J Craniofac Surg 24:344-5
Chan, Charles K F; Lindau, Paul; Jiang, Wen et al. (2013) Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells. Proc Natl Acad Sci U S A 110:12643-8
Chung, Michael T; Liu, Chunjun; Hyun, Jeong S et al. (2013) CD90 (Thy-1)-positive selection enhances osteogenic capacity of human adipose-derived stromal cells. Tissue Eng Part A 19:989-97
Behr, Bjorn; Sorkin, Michael; Lehnhardt, Marcus et al. (2012) A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model. Tissue Eng Part A 18:1079-86
Behr, Bjorn; Sorkin, Michael; Manu, Alina et al. (2011) Fgf-18 is required for osteogenesis but not angiogenesis during long bone repair. Tissue Eng Part A 17:2061-9
Kwan, Matthew D; Sellmyer, Mark A; Quarto, Natalina et al. (2011) Chemical control of FGF-2 release for promoting calvarial healing with adipose stem cells. J Biol Chem 286:11307-13
Li, Shuli; Quarto, Natalina; Longaker, Michael T (2010) Activation of FGF signaling mediates proliferative and osteogenic differences between neural crest derived frontal and mesoderm parietal derived bone. PLoS One 5:e14033
Behr, Bjorn; Panetta, Nicholas J; Longaker, Michael T et al. (2010) Different endogenous threshold levels of Fibroblast Growth Factor-ligands determine the healing potential of frontal and parietal bones. Bone 47:281-94