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Microarray analysis of gene expression in osteoblasts from patients with osteoporosis (OP) and osteoarthritis (OA) showed that 115 genes were robustly differentially expressed (P<0.05). Functional annotation clustering revealed cell adhesion to be the gene ontology classification most likely to be associated with this gene list. In addition scrutiny of the list revealed several genes with strong biological support for the involvement in bone homeostasis (FOSL1, BMPR2 and TGFBR1). Real -time PCR validated the trends seen in the microarray analysis, but failed to reach statistical significance for any of the genes examined. This analysis supports the value and potential of larger scale comparison of gene expression in OA and OP osteoblasts as a method for identifying novel factors involved in bone homeostasis. The cannabinoid system has recently been identified as involved in the regulation of bone homeostasis. In vitro investigation revealed that although cannnabinoid receptor agonists N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG) and JWH015 had no effect on metabolic activity, cell number, or alkaline phosphatase activity of calvarial mouse osteoblasts there were changes in gene expression. RankL expression was reduced relative to Opg expression by both JWH015 and AEA. Preliminary results indicate that JWH015 was also capable of increasing PPARγ expression which could alter the balance of osteoblastic and adipocytic differentiation of mesenchymal stem cells (MSC). This could have implications for use of these drugs in vivo. Using the 3T3-F442A cell line to develop a model of MSC differentiation highlighted difficulties associated with using cell models. Necessary additional factors required to induce differentiation of a cell line compared to a primary cell make interpretation of results more complicated. This model also highlighted that alkaline phosphatase and osteocalcin (markers usually used to identify osteogenic differentiation) were expressed during adipocytic differentiation. Future use of such markers in MSC models should be closely scrutinized.

La osteoporosis es una de las enfermedades crónicas más prevalentes en la edad adulta, siendo responsable de una alta tasa de morbilidad y mortalidad. La aparición de la osteoporosis en mujeres posmenopáusicas debido principalmente a la disminución de los niveles séricos de estrógeno ha sido propuesta como un factor de riesgo de la enfermedad periodontal, sin embargo, la relación entre estas dos enfermedades no está del todo clara. El objetivo del presente estudio fue el de comparar el grado de periodontitis entre mujeres posmenopáusicas con osteoporosis y mujeres posmenopáusicas sin osteoporosis que acudieron al Servicio de Reumatología del Hospital Nacional Edgardo Rebagliati Martins durante diciembre del año 2003. La población estudiada incluyó 40 mujeres posmenopáusicas con osteoporosis y 40 mujeres posmenopáusicas sin osteoporosis, con edades entre los 50 y 55 años (edad promedio: grupo con osteoporosis: 52.40 ± 1.22 años, grupo sin osteoporosis: 52.25 ± 1.13 años). La condición de osteoporosis fue determinada por la medición de la Densidad Mineral Ósea (DMO) mediante Absorciometría de Energía Dual de Rayos X (DEXA) en la región de la columna lumbar. La severidad de la periodontitis fue representada por el Índice de Enfermedad Periodontal de Ramfjord (PDI) y la Pérdida de Adherencia Clínica (PAC). Otras mediciones periodontales incluyeron la cuantificación de placa y cálculo expresados a través del Índice de Higiene Oral Simplificado de Green y Vermillon (IHO-S). Los exámenes periodontales y de DEXA fueron realizados por examinadores calibrados. Se utilizó la prueba t-student para comprobar la relación entre el grado de periodontitis y la osteoporosis. El presente estudio encontró una diferencia estadísticamente significativa del índice de enfermedad periodontal entre mujeres posmenopáusicas con y sin osteoporosis (p<0.05). De otro lado, al caracterizar la asociación entre el índice de enfermedad periodontal y la pérdida de adherencia clínica con los niveles clínicos de higiene oral para ambos grupos de mujeres, se encontraron diferencias estadísticamente significativas en el grupo de mujeres posmenopáusicas con osteoporosis (p<0.05), a diferencia del grupo de mujeres posmenopáusicas sin osteoporosis (p>0.05). Estos hallazgos sugieren que existe una relación directa entre la osteoporosis y la gravedad de la periodontitis en mujeres posmenopáusicas, es decir que la condición de osteoporosis en este grupo de mujeres está asociada a un mayor grado de severidad de la periodontitis, luego de haber controlado factores como la edad, edad posmenopáusica, raza e higiene oral. Así mismo, en presencia de niveles clínicos deficientes de higiene oral, las mujeres posmenopáusicas con osteoporosis presentan significativamente un mayor grado de periodontitis en comparación con aquellas con mejores niveles clínicos de higiene oral. Palabras clave: Densidad mineral ósea, pérdida de adherencia clínica, índice de enfermedad periodontal, índice de higiene oral simplificado, osteoporosis, posmenopausia, periodontitis, enfermedad periodontal. / Osteoporosis is one of the more prevalent chronic disease in the adult age, being responsible for a high rate of morbility and mortality. The appearing of the osteoporosis in postmenopausal women owed mainly to the diminution of blood estrogen levels has been propose like a risk factor of the periodontal disease, however, the relation between these two diseases is not absolutely clear. The objective of the present study was to compare the degree of periodontitis between postmenopausal women with osteoporosis and postmenopausal women without osteoporosis who went to the Service of Rheumatology of the Edgardo Rebagliati Martins National Hospital during December 2003. The studied population included 40 postmenopausal women with osteoporosis and 40 postmenopausal women without osteoporosis, with ages between 50 and 55 years old (average age: group with osteoporosis: 52.40 ± 1,22 years old, group without osteoporosis: 52.25 ± 1,13 years old). The condition of osteoporosis was determined by the measurement of the Bone Mineral Density (DMO) by means of Dual Energy X Ray Absorciometry (DEXA) in the region of the lumbar column. The severity of the periodontitis was represented by the Ramfjord´s Periodontal Disease Index (PDI) and the Loss of Clinical Attachment (PAC). Other periodontal measurements included the quantification of plaque and tartar through the Green and Vermillion’s Oral Hygiene Simplified Index (IHO-S). Periodontal and DEXA examinations were made by calibrated examiners. The t-student test was used to verify the relation between the degree of periodontitis and the osteoporosis. The present study found a statistically significant difference of the Index of Periodontal Disease between postmenopausal women with and without osteoporosis (p<0.05). In addition, when the association between the Index of Periodontal Disease and the Loss of Clinical Attachment with Clinical Levels of Oral Hygiene for both groups of women was assessed, statistically significant differences were found in the group of postmenopausal women with osteoporosis (p<0.05), but no differences were found in the group of postmenopausal women without osteoporosis (p>0.05). These findings suggest that exists a direct relation between the osteoporosis and the severity of the periodontitis in postmenopausal women, it means that the condition of osteoporosis in this group of women is associated to a higher degree of periodontitis, after the control of factors like age, postmenopausal age, race and oral hygiene. Additionally, in presence of deficient clinical levels of oral hygiene, postmenopausal women with osteoporosis present a higher degree of periodontitis in comparison with those with better clinical levels of oral hygiene. Key words: Bone mineral density, loss of clinical attachment, index of periodontal disease, simplified index of oral hygiene, osteoporosis, postmenopausal, periodontitis, periodontal disease.

by Chan Yat Heung. / Thesis submitted in: December 1998. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 81-88). / Abstract also in Chinese. / Declaration --- p.2 / Abstract --- p.3 / Abstract in Chinese --- p.5 / Acknowledgements --- p.7 / Chapter Chapter 1. --- Introduction --- p.12 / Chapter Chapter 2. --- Literature review on the prevalence of vertebral deformity --- p.16 / Chapter 2.1 . --- Prevalence of vertebral deformity in women --- p.16 / Chapter 2.2. --- Prevalence of vertebral deformity in men --- p.21 / Chapter Chapter 3. --- Literature review on the risk factors for osteoporosis and vertebral deformity --- p.25 / Chapter 3.1. --- Dietary calcium intake --- p.25 / Chapter 3.1.1 --- Epidemiological studies --- p.25 / Chapter 3.1.2 --- Intervention studies --- p.26 / Chapter 3.1.3 --- Calcium intake and osteoporosis in Chinese --- p.28 / Chapter 3.2. --- Physical Activity --- p.30 / Chapter 3.2.1 --- Epidemiological studies --- p.30 / Chapter 3.2.2 --- Intervention studies --- p.33 / Chapter 3.2.3 --- Physical activity and osteoporosis in Chinese --- p.34 / Chapter 3.3. --- Cigarette smoking --- p.35 / Chapter 3.4. --- Alcohol consumption --- p.37 / Chapter Chapter 4. --- Subjects and Methods --- p.39 / Chapter 4.1. --- Objectives --- p.39 / Chapter 4.2. --- Study Subjects --- p.40 / Chapter 4.3. --- Radiology and digitization protocol --- p.41 / Chapter 4.4. --- Diagnosis of vertebral deformity --- p.43 / Chapter 4.5. --- Definition of cases and controls --- p.48 / Chapter 4.6. --- Questionnaire and measurement of risk factors --- p.49 / Chapter 4.6.1. --- Dietary calcium intake --- p.49 / Chapter 4.6.2. --- Physical activity --- p.49 / Chapter 4.6.3. --- Cigarette smoking --- p.50 / Chapter 4.6.4. --- Alcohol consumption --- p.50 / Chapter 4.7. --- Pilot study --- p.51 / Chapter 4.8. --- Statistical methods --- p.52 / Chapter Chapter 5. --- Results of Prevalence study --- p.54 / Chapter 5.1 . --- Demographic characteristics --- p.54 / Chapter 5.2. --- Vertebral height and vertebral height ratio --- p.55 / Chapter 5.3. --- Distribution of deformity --- p.59 / Chapter 5.4. --- Comparison of prevalence between Chinese and Caucasian populations --- p.61 / Chapter Chapter 6. --- Results of study on risk factors --- p.62 / Chapter 6.1. --- Dietary calcium intake --- p.62 / Chapter 6.2. --- Physical activity --- p.63 / Chapter 6.3. --- Cigarette smoking --- p.65 / Chapter 6.4. --- Alcohol consumption --- p.67 / Chapter 6.5. --- Results of Multiple logistic regression --- p.69 / Chapter Chapter 7. --- Discussion --- p.70 / Chapter 7.1. --- Study sample --- p.70 / Chapter 7.2. --- Digitization method and definition of vertebral fracture --- p.71 / Chapter 7.3. --- Prevalence of vertebral deformity in Chinese men --- p.72 / Chapter 7.4. --- Risk factors --- p.74 / Chapter 7.4.1. --- Calcium intake --- p.74 / Chapter 7.4.2. --- Physical activity --- p.75 / Chapter 7.4.3. --- Cigarette Smoking --- p.77 / Chapter 7.4.4. --- Alcohol consumption --- p.78 / Chapter Chapter 8. --- Conclusion --- p.80 / Reference --- p.81 / Appendix --- p.89

Sternal malunion is a complication resulting in displacement of the sternal halves following open heart surgery. Currently, little is known about the effectiveness of alternative fixation systems under physiologically relevant loading scenarios. The goal of this study was to mechanically test several currently marketed sternal fixation devices and compare them to a prototype device in different loading conditions to simulate sitting up or breathing. Each system showed unique differences in cost, failure mode and efficiency; however, no statistical difference in failure load or displacement was observed between the testing groups.

The differentiation of osteoblasts and bone marrow adipocytes are closely associated yet mutually exclusive processes that are essential for maintaining bone homeostasis. Various diseases have been shown to develop once the delicate balance between adipogenesis and osteoblastogenesis is disrupted. Investigating the underlying molecular mechanisms of the osteoblasto-adipogenic switch under osteoporotic conditions will facilitate our understanding of the pathogenesis of osteoporosis and may eventually lead to the development of clinical therapeutic approaches for this life-threatening disease. While changes in cell morphology and cytoskeletal integrity can alter pre-committed mesenchymal stem cell (MSC) differentiation of certain lineages, previous studies have shown that cellular morphological changes can affect the early commitment of pluripotent MSCs via modulation of Ras homolog gene family, member A (RhoA) activity. The RhoA pathway regulates actin polymerization to promote the incorporation of globular-actin (G-actin) into filamentous-actin (F-actin). Actin polymerization releases G-actin bound myocardin-related transcription factors (MRTFs), which translocate to the nucleus and co-activate serum response factor (SRF) target gene expression. Exactly how the RhoA-actin-MRTF-SRF circuit is involved in the regulation of early commitment of MSCs remains poorly understood. Here we show that global MRTFA knockout mice (MRTFA KO) exhibited lower body weight, shorter femur and tibia lengths, and decreased trabecular bone volume. Furthermore, bone marrow MSCs isolated from MRTFA KO mice showed increased adipogenesis and brown fat gene expression as well as compromised osteoblastogenic differentiation as compared to WT controls. Treatment of WT bone marrow MSCs with the SRF inhibitor, CCG1423, mimicked these effects in that the compound inhibited osteoblastogenesis and promoted adipogenesis. Over-expression of MRTFA or SRF inhibited adipogenesis and enhanced osteoblastogenesis in C3H/10T1/2 cell lines, whereas over-expression of dominant-negative MRTFA or SRF variants had the opposite effects. In conclusion, our study identified MRTFA as a crucial regulator of skeletal homeostasis via regulating the balance between adipogenic and osteoblastogenic differentiation of the MSCs. Furthering our understanding of how the RhoA-actin-MRTFA-SRF circuit is involved in regulating the fate commitment of MSCs may ultimately lead to novel therapeutic strategies for treating osteoporosis and obesity.

Orientador: Roberta Okamoto / Coorientadora: Mariza Akemi Matsumoto / Banca: Sonia Regina Panzarini / Banca: Ana Cláudia Rossi / Resumo: Objetivos: Avaliar a influência da teriparatida, administrada sistemicamente, nas características morfológicas e estruturais do osso reparacional formado durante o processo de reparo alveolar em ratos com osteoporose induzida (orquiectomizados). Materiais e Métodos: Foram utilizados 48 ratos divididos 3 em grupos discriminados a seguir: 16 ratos orquiectomizados tratados com teriparatida, 16 ratos orquiectomizados sem tratamento e 16 ratos sham. Deste modo, dividindo-se 8 ratos para análise histológica e para a análise imuno-histoquímica que foi feita através da expressão das proteínas TRAP, osteocalcína, e WNT, com período de eutanásia em 42 dias (tecidos descalcificados), e 8 ratos para análise microtomográfica (tecidos calcificados), nesta análise o período de eutanásia foi de 60 dias pós exodôntico. Os dados quantitativos foram submetidos ao teste de normalidade e este indicou um teste estatístico mais adequado (paramétrico VS não paramétrico). Foi adotado para todos os testes nível de significância de 5%. Resultados: A análise histológica mostrou melhores padrões de neoformação óssea para o grupo ORQTRAT com maior quantidade de tecido mineralizado e pouco tecido conjuntivo. Os resultados imunohistoquímicos novamente mostraram um padrão de reparo melhor no grupo ORQTRAT com marcações mais intensas de wnt e osteocalcína e marcações mais fracas de trap. Aos resultados da microtomografia novamente o grupo ORQTRAT se demostrou melhor que os demais, com maior volume ósseo (B... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Orientador: Roberta Okamoto / Coorientador: Roelf Justino Cruz Rizzolo / Banca: Hugo Nary Filho / Banca: Mariza Matsumoto / Banca: Ronaldo Célio Mariano / Banca: Idelmo Rangel Garcia Junior / Resumo: O objetivo deste estudo foi avaliar o reparo ósseo na interface osso/implante em ratas com osteoporose induzida. As ratas submetidas à ovariectomia bilateral foram alimentadas com uma dieta pobre em cálcio. Dois grupos receberam tratamento medicamentoso (raloxifeno [OVX RAL] ou alendronato [OVX ALE]) e outro grupo não recebeu nenhuma medicação (OVX ST). O grupo controle foi submetido à cirurgia fictícia e foi alimentado com uma dieta normal (SHAM DN). Cada animal recebeu um implante em cada tíbia. Os animais foram eutanasiados após 14 ou 42 dias. Foram realizadas as análises biomecânica (torque reverso), extensão linear de contato osso/implante (ELCOI) e dinâmica óssea periimplantar pela proporção dos fluorocromos calceína/alizarina, aplicando-se a análise de variância ANOVA e o pós-teste de Tukey (p<0,05). A imunoistoquímica marcou a precipitação de osteoprotegerina (OPG), RANKL, TRAP e osteocalcina (OC). O medicamento RAL melhorou o reparo ósseo periimplantar, em que o grupo ALE foi semelhante ao grupo OVX ST. Não houve diferenças estatisticamente significativas no torque reverso (p = 0,861), na precipitação dos fluorocromos (calceína/alizarina) e na ELCOI entre os grupos OVX RAL e grupo controle - SHAM DN (p > 0,05). As imunomarcações de OPG e RANKL foram similares para os grupos RAL e SHAM; houve moderada expressão de OC aos 14 dias. A TRAP foi marcada intensamente aos 42 dias para o grupo OVX. Portanto, o raloxifeno melhorou o reparo ósseo periimplantar de ratas osteoporóticas, sugerindo a sua indicação no tratamento da osteoporose. / Abstract: The aim of this study was to evaluate the bone healing in bone/implant interface in rats with induced osteoporosis. The rats underwent bilateral ovariectomy were fed a diet low in calcium. Two groups received drug treatment (raloxifene [OVX RAL] or alendronate [OVX ALE]) and the other group received no medication (OVX NT). The control group underwent sham surgery and was fed a normal diet (SHAM ND). Each animal received an implant on the tibia. The animals were euthanized after 14 or 42 days. The biomechanical analysis (reverse torque), linear extension contact bone / implant (BIC) and bone dynamics periimplantar by the proportion of fluorochrome calcein/alizarin, applying the ANOVA and Tukey's post-test (p<0.05). Immunohistochemistry marked precipitation of osteoprotegerin (OPG), RANKL, TRAP and osteocalcin (OC). The RAL improved drug peri-implant bone repair, wherein the ALE OVX group was similar to the ST group. There were no statistically significant differences in reverse torque (p = 0.861), precipitation of fluorochromes (calcein/alizarin) and BIC between OVX RAL and control groups - SHAM ND (p> 0.05). The immunostaining of OPG and RANKL were similar to RAL and SHAM groups; there was moderate OC expression at 14 days. TRAP was marked intensely at 42 days for the OVX group. Therefore, raloxifene improved peri-implant bone repair of osteoporotic rats, suggesting its indication in the treatment of osteoporosis. / Doutor