Recent research suggests that diversity in craniofacial morphology is produced by a complex interaction of environmental variables including 1) muscle function, 2) genetic factors related to skull growth, 3) timing and heritability of suture fusion (cessation of growth of the joints connecting the bones of the skull), 4) growth and morphology of the brain, and 5) other non-genetic factors including hormones of the endocrine system. How these factors interact in cranial growth and development is not well understood. This dissertation investigated the influence of androgenic hormone on suture bone biology. Methodology used including in vitro cellular challenges, protein analyses, and in vivo therapies. The work described here utilized a large sample size to establish the role of testosterone as a modulator of bone morphogenetic protein and subsequent effects on osteoblast differentiation. Testosterone increased the effect of BMP on osteoblasts, increasing differentiation. The increased differentiation effect was successfully blocked using flutamide, an androgen receptor blocker. Bone cells harvested from non suture calvaria in craniosynostotic rabbits were most susceptible to flutamide administration. The presence of androgen receptors in cells harvested from the suture and non suture bone of craniosynostotic or wild type rabbits could not be confirmed due to a lack of an effective antibody. In vivo administration of flutamide to the coronal suture of craniosynostotic rabbits resulted in greater growth across the coronal suture. However, no correction of craniofacial growth was observed. These results suggest 1) an alternative pathway for dihydrotestosterones and testosterones effect on the suture, similar to the adrenal androgens, via the MAP kinase pathway, 2) lack of an effective delivery system of the flutamide treatment, or 3) that an androgen receptor blocker-based therapy is not effective for delaying the eventual fusion of the coronal suture in this model.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07152009-161413 |
| Date | 30 September 2009 |
| Creators | Cray Jr., James John |
| Contributors | Gregory M. Cooper, Ph.D., Mark P. Mooney, Ph.D., David Finegold, M.D., Richard Scaglion, Ph.D., Michael I. Siegel, Ph.D. |
| 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-07152009-161413/ |
| 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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