In cases of craniosynostosis, defined as the premature fusion of the cranial sutures, there is a need to inhibit bone formation in small calvarial defects to avoid the occurrence of postoperative resynostosis. Similarly, reconstruction of bone in the craniofacial skeleton following injury or tumor resection necessitates controlled bone regeneration to avoid bone overgrowth. Bone morphogenetic proteins (BMPs) are potent bone inducing growth factors that are expressed during normal bone healing. Noggin is an extracellular antagonist to BMPs. This work studied the use of Noggin to prevent postoperative resynostosis in a rabbit model of human nonsyndromic craniosynostosis via protein therapy. A mouse model of a healing suturectomy was also developed. This model was used to study the effects of Noggin ex vivo gene therapy on the inhibition of postoperative resynostosis. Finally, the ability of Noggin to inhibit bone overgrowth and improve BMP4-induced bone formation was tested. The work presented here demonstrates that a single dose of Noggin protein is capable of inhibiting resynostosis and improving craniofacial growth after surgery to correct craniosynostosis in rabbits. Noggin delivered through ex vivo gene therapy was able to inhibit bone formation in a novel mouse model. Also, the implantation of Noggin expressing cells along with BMP4 expressing cells reduced ectopic bone formation and improved bone density. These results suggest that Noggin therapy may be useful for the inhibition of postoperative resynostosis in children with craniosynostosis. Furthermore, by recreating naturally occurring expression patterns (for example, both Noggin and BMP4), we may be able to control the size, shape and quality of bone formed by biologically-driven therapies.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11292006-152436 |
| Date | 31 January 2007 |
| Creators | Cooper, Gregory M. |
| Contributors | Partha Roy, PhD, Kacey Marra, Johnny Huard, PhD, Mark P. Mooney, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11292006-152436/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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