Estrogen-receptor-related receptor gamma, ERRγ, is highly expressed in cartilage and upregulates the chondrogenic transcription factor, Sox9, in a chondrocytic cell line. To assess the effect of increasing ERRγ activity on cartilage in vivo, we generated transgenic animals driving ERRγ expression with a chondrocyte-specific promoter. I verified that one transgenic line exhibited 26% increased ERRγ protein at E14.5. No major morphological defects were seen at this stage, but I observed significant reduction in the size of the appendicular skeleton in P7 mice, such that all elements of the appendicular skeleton were significantly reduced by 4 – 10%. I continued the phenotype analysis at the histological level and found that the P7 animals displayed significantly reduced growth plate height, caused by deficiencies in the size of the proliferative and hypertrophic zones of the growth plate. This suggests a previously unknown role for ERRγ in regulating endochondral ossification in growth plate chondrocytes.

As the prevalence of osteoporosis is expected to increase over the next few decades, the development of novel therapeutic strategies to combat this disorder becomes clinically imperative. These efforts draw extensively from an expanding body of knowledge pertaining to the physiologic mechanisms of skeletal homeostasis. To this body of knowledge, we contribute that cells of hematopoietic lineage may play a crucial role in balancing osteoblastic bone formation against osteoclastic resorption. Specifically, our laboratory has previously demonstrated that megakaryocytes can induce osteoblast proliferation in vitro, but do so only when direct cell-to-cell contact is permitted. To further investigate the nature of this interaction, we have effectively neutralized several adhesion molecules known to function in the analogous interaction of megakaryocytes with another cell-type of mesenchymal origin - the fibroblast. Our findings implicate the involvement of fibronectin/RGD-binding integrins including á3â1 (VLA-3) and á5â1 (VLA-5) as well as glycoprotein IIb (CD41), all of which are known to be expressed on megakaryocyte membranes. Furthermore, we demonstrate that IL-3 can enhance megakaryocyte-induced osteoblast activation in vitro, as demonstrated in the megakaryocyte-fibroblast model system. Taken together, these results suggest that although their physiologic and clinical implications are very different, these two models of hematopoietic-mesenchymal cell activation are mechanistically analogous.

Osteoporosis is a major public health concern with origins in childhood and is potentially linked to childhood obesity. This study used novel approaches in bone imaging to characterize skeletal development in girls and to assess the influence of whole body and regional soft tissue composition on bone material, structural and geometric properties, the primary determinants of bone strength, controlling for important covariates such as maturation, diet and physical activity. Prospective analyses were conducted to assess associations between measures of total body fat (TBFM) and android fat masses (AFM) and skeletal muscle fat (SMF) content on bone mineral content, density and strength. The results showed that higher TBFM and AFM were inversely associated with changes in cortical bone sites of the femur and tibia. These findings suggest that gains in abdominal adiposity during the pre- and early- pubertal years may contribute to suboptimal bone development and skeletal fragility later in life. The analyses also showed inverse associations between baseline muscle density of the thigh and calf with 2-year changes in bone strength and bone density of the metaphyseal and diaphyseal sites of the femur and tibia. This paradoxical relationship between SMF and bone outcomes was explained by subsequent analyses showing that girls exhibiting larger gains in muscle density experienced larger increases in bone density and strength compared to girls who did not significantly increase muscle density. These findings suggest that fatty infiltration of skeletal muscle contributes to suboptimal bone development in peri-pubertal girls. Further longitudinal analyses were conducted to examine the individual effects of the muscle-bone unit components on 2-year changes in bone strength. These results showed that muscle size contributed to gains in bone strength, independent of its mechanostat effect on BMC. These results underscore the importance of muscle size for promoting bone development and bone strength during growth. A final set of analyses were conducted to examine the effects of dietary fatty acids on bone development. The results of these analyses suggest that while decreasing intakes of AA n-6 FA may benefit bone health, higher intakes n-3 FAs may benefit tibia bone density development in young girls.

No description available.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第23834号 / 薬科博第149号 / 新制||薬科||16(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 竹島 浩, 教授 金子 周司, 教授 土居 雅夫 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept 22, 2008). Includes bibliographical references (p. 42-45).

Made available in DSpace on 2014-06-11T19:29:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-08-01Bitstream added on 2014-06-13T20:38:33Z : No. of bitstreams: 1 tanaka_jlo_me_sjc.pdf: 970159 bytes, checksum: a140b3dc5374016a65756a5449931155 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / As vértebras cervicais vêm sendo cada vez mais empregadas para a análise de maturação óssea em Ortodontia e Ortopedia Funcional dos Maxilares. Visto que as mudanças que ocorrem nessas estruturas são sutis, comparou-se, por meio de medidas, sete razões obtidas nas vértebras cervicais C2, C3 e C4 em radiografias cefalométricas laterais entre as fases da curva de crescimento puberal de 95 pacientes do sexo feminino e 136 do masculino. Os resultados demonstraram que a razão 1 (C2Conc/C2PI-C2AI) difere estatisticamente entre os grupos A/B e C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 2 (C3Conc/C3PI-C3AI) difere estatisticamente entre os grupos A/B/C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 3 (C4Conc/C4PI-C4AI) difere estatisticamente entre os grupos B/C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 4 (C3AS-C3AI/C3PS-C3PI) difere estatisticamente entre os grupos B/C nos indivíduos do sexo masculino e entre B/C/E nos do feminino; a razão 5 (Altura do corpo de C3/Comprimento do corpo de C3) difere estatisticamente entre os grupos A/C/D/E nos indivíduos do sexo masculino e entre A/C e D/E nos do feminino; a razão 6 (C4ASC4AI/ C4PS-C4PI) difere estatisticamente entre os grupos B/C nos indivíduos do sexo masculino e entre os grupos B/C/D nos do feminino; e a razão 7 (Altura do corpo de C4/Comprimento do corpo de C4) difere estatisticamente entre os grupos C/D nos indivíduos do sexo masculino e entre A/C/D nos do feminino. / The cervical vertebrae have been employed on the assessment of the bone maturation stage on the last years. Since the changes on these structures are subtle, seven ratios obtained from measurements on lateral cephalometric radiographs of the second, third and fourth cervical vertebrae were compared among the phases of the pubertal growth curve of 95 male and 136 female patients. The results demonstrated that ratio 1 (C2Conc/C2PI-C2AI) differs statistically between groups A/B and C/D on male subjects and between groups B/C and D/E on female subjects; ratio 2 (C3Conc/C3PI-C3AI) is statistically different among groups A/B/C/D on males and between B/C and D/E on females; ratio 3 (C4Conc/C4PI-C4AI) differs statistically among groups B/C/D on males and between B/C and D/E on females; ratio 4 (C3AS-C3AI/C3PS-C3PI) is statistically different between groups B/C on males and among B/C/E on females; ratio 5 (Height of the body of C3/Length of the body of C3) differs statistically among groups A/C/D/E on males and between A/C and D/E on females; ratio 6 (C4AS-C4AI/C4PS-C4PI) differs statistically between groups B/C on male subjects and among groups B/C/D on females; and ratio 7 (Height of the body of C4/Length of the body of C4) differs statistically between groups C/D on males and among A/C/D on females.

Orientador: Edmundo Medici Filho / Banca: Emiko Saito Arita / Banca: Julio Cezar de Melo Castilho / Resumo: As vértebras cervicais vêm sendo cada vez mais empregadas para a análise de maturação óssea em Ortodontia e Ortopedia Funcional dos Maxilares. Visto que as mudanças que ocorrem nessas estruturas são sutis, comparou-se, por meio de medidas, sete razões obtidas nas vértebras cervicais C2, C3 e C4 em radiografias cefalométricas laterais entre as fases da curva de crescimento puberal de 95 pacientes do sexo feminino e 136 do masculino. Os resultados demonstraram que a razão 1 (C2Conc/C2PI-C2AI) difere estatisticamente entre os grupos A/B e C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 2 (C3Conc/C3PI-C3AI) difere estatisticamente entre os grupos A/B/C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 3 (C4Conc/C4PI-C4AI) difere estatisticamente entre os grupos B/C/D nos indivíduos do sexo masculino e entre B/C e D/E nos do feminino; a razão 4 (C3AS-C3AI/C3PS-C3PI) difere estatisticamente entre os grupos B/C nos indivíduos do sexo masculino e entre B/C/E nos do feminino; a razão 5 (Altura do corpo de C3/Comprimento do corpo de C3) difere estatisticamente entre os grupos A/C/D/E nos indivíduos do sexo masculino e entre A/C e D/E nos do feminino; a razão 6 (C4ASC4AI/ C4PS-C4PI) difere estatisticamente entre os grupos B/C nos indivíduos do sexo masculino e entre os grupos B/C/D nos do feminino; e a razão 7 (Altura do corpo de C4/Comprimento do corpo de C4) difere estatisticamente entre os grupos C/D nos indivíduos do sexo masculino e entre A/C/D nos do feminino. / Abstract: The cervical vertebrae have been employed on the assessment of the bone maturation stage on the last years. Since the changes on these structures are subtle, seven ratios obtained from measurements on lateral cephalometric radiographs of the second, third and fourth cervical vertebrae were compared among the phases of the pubertal growth curve of 95 male and 136 female patients. The results demonstrated that ratio 1 (C2Conc/C2PI-C2AI) differs statistically between groups A/B and C/D on male subjects and between groups B/C and D/E on female subjects; ratio 2 (C3Conc/C3PI-C3AI) is statistically different among groups A/B/C/D on males and between B/C and D/E on females; ratio 3 (C4Conc/C4PI-C4AI) differs statistically among groups B/C/D on males and between B/C and D/E on females; ratio 4 (C3AS-C3AI/C3PS-C3PI) is statistically different between groups B/C on males and among B/C/E on females; ratio 5 (Height of the body of C3/Length of the body of C3) differs statistically among groups A/C/D/E on males and between A/C and D/E on females; ratio 6 (C4AS-C4AI/C4PS-C4PI) differs statistically between groups B/C on male subjects and among groups B/C/D on females; and ratio 7 (Height of the body of C4/Length of the body of C4) differs statistically between groups C/D on males and among A/C/D on females. / Mestre