Genomic Analysis of Bone Mineral Density and Investigation on the Use of Testosterone for Fracture Repair

Autor: Bi Hua Cheng, 鄭碧華
Rok vydání: 2013
Druh dokumentu: 學位論文 ; thesis
Popis: 101
The purpose of this thesis research is to investigate genetic factors that affect bone mineral density (BMD) and to develop novel methods to treat bone fractures. This research is timely as the incidence of osteoporosis and its related fracture is increasing, mainly due the increase in aged population, and that of hip fracture in Taiwanese women is currently the highest in Asia. The social and economic impact of osteoporosis is equivalent to that of hypertension, stoke, and breast cancer. Since the decrease in estrogen levels in post menopausal women is a major factor in osteoporosis, this research focused on single-nucleotide polymorphism of the estrogen receptor 1 (ESR1) gene in relation to BMD. In the first part of the study, 5 ESR1 SNPs and 3 RANKL SNPs in 467 postmenopausal Taiwanese were genotyped, and the results were correlated with bone mineral density (BMD). Subjects with the ESR1 Crs1884054 allele were found to have a lower BMD at LS2-4/Lateral view, and those with the ESR1 haplotype Trs2234693-Ars922996 had a higher risk for low BMD also at LS2-4/Lat. In addition, subjects without the RANKL haplotype Grs2148072-Crs2200287-Grs922996 had a higher risk for low BMD at LS1-4/AP. In the second part of the study, the genes that co-express with ESR1 in various tissues were identified to investigate whether they affect ESR1 expression using the GeneChaser search program. The differential expression of 5 transcription factors (TEF-1, NF-1, SRF, ICSBP, and CIZ) and one miRNAs (hsa-miR519a) were found to correlate with that of ESR1. In the third part of the study, thirty-eight SNPs in NFKB, 37 in RANK, 61 in RANKL, and 58 in OPG in 1,813 women and 1,375 men (mean age 62.5 years) in the Framingham Osteoporosis Study database were investigated to determine their relationship with lumbar spine or femur neck BMD. Significant associations between gene-gene interaction and femur neck BMD were found in OPG and RANK in women. In the last part of the study, testosterone, bone morphogenetic protein-2 (BMP-2), and a combination of both were assessed for effects on the healing of critical-size segmental bone defects. The results showed that testosterone is as effective as BMP-2 in promoting the healing of critical-size segmental defects and that combination therapy with testosterone and BMP-2 is superior to single therapy. Taken together, results of this thesis research allow a better understanding of the effects of sex hormones on BMD and the possibility of using testosterone as a therapeutic agent for fracture repair.
Databáze: Networked Digital Library of Theses & Dissertations
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