Orientador: Maria Beatriz Duarte Gavião / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia / Made available in DSpace on 2018-08-14T23:52:51Z (GMT). No. of bitstreams: 1 Gambareli_FlaviaRiqueto_D.pdf: 5604961 bytes, checksum: c8fb1e1512acbc39d6fbb9d36dfab000 (MD5) Previous issue date: 2009 / Resumo: A Doença de Gaucher (DG) e uma doença de origem genética, autossomica recessiva, causada por mutações do gene da glucocerebrosidase, o qual codifica a enzima beta-glucocerebrosidase, determinando deficiência na produção e/ou na sua atividade. O objetivo desse estudo foi avaliar a saúde oral, a qualidade vida, as condições maxilares e as características craniofaciais de indivíduos com DG. Dezessete pacientes sob tratamento medico no Centro de Hematologia e Hemoterapia (Hemocentro) da Universidade Estadual de Campinas (Unicamp) participaram desse estudo. Destes, oito eram crianças, entre 7 e 15 anos, e nove adultos, entre 27 e 53 anos. Todos os pacientes receberam exame clinico oral completo, avaliando-se tecidos moles e dentes cariados, perdidos ou obturados, deciduos (ceo) e permanentes (CPOD). Nos pacientes adultos realizou-se exame periodontal, avaliando-se o nível de inserção clinica (NIC), a profundidade de sondagem (PS), a posção da gengiva marginal (PGM), o índice de placa visível (PV) e de sangramento gengival (SG). Realizou-se exame radiográfico panorâmico para avaliar as condições ósseas da maxila e mandíbula, e o momento de erupção da dentição permanente nas crianças. A radiografia lateral foi realizada para avaliar as características craniofaciais pela analise cefalometrica. O crescimento das crianças foi avaliado pela comparação do peso e da altura com gráficos padrões. A idade óssea foi estimada pela radiografia do punho e da mao. A influencia da saúde oral sobre a qualidade de vida foi avaliada por questionários auto-administrados pelas crianças - Child Perception Questionnaire - CPQ 8-10 anos e CPQ 11-14 anos; e o questionário Oral Health Impact Profile - OHIP 49 - foi usado para os pacientes adultos. Aplicou-se teste Wilcoxon para se avaliar o momento de erupção dos dentes permanentes e para comparar as variáveis cefalometrica ao padrão. O ceo médio encontrado foi de 2,67 e o CPOD de 0,75. Para os pacientes adultos, um alto índice CPOD (20,44), leve doença gengival e moderada doença periodontal foram observados. As crianças mostraram retardo no crescimento e diferença de 13 e 16 meses, em media, entre a idade cronológica e a idade óssea, na primeira e segunda avaliação, respectivamente. Considerando a idade óssea, erupção precoce foi observada em 5 pacientes, principalmente nos incisivos centrais e laterais. Considerando a idade cronológica, 7 pacientes exibiram erupção atrasada, significante para o segundo pré-molar. Os achados radiográficos mais encontrados nos maxilares foram rarefação generalizada, borramento do canal mandibular e perda da estrutura trabecular. Pela analise cefalometrica, bservouse que seis crianças mostraram valores lineares de crescimento craniofacial maiores quando comparados ao padrão. O escore médio total do CPQ 8-10 anos foi 17, mostrando moderado impacto da saúde oral na qualidade de vida das crianças nessa faixa etária. O escore médio total do CPQ 11-14 anos foi 38. Os adultos demonstraram impacto expressivo na qualidade de vida relacionada a saúde oral. Concluiu-se que as crianças com DG apresentaram boa saúde oral, erupção precoce de alguns grupos dentários, importante alterações nos maxilares e alterações no crescimento craniofacial. Embora não tenham apresentado saúde oral deficiente, algumas condições orais interferiram na qualidade de vida. Os pacientes adultos apresentaram envolvimento ósseo dos maxilares, pobre saúde oral e consequentemente prejudicada qualidade de vida relacionada a saúde oral. / Abstract: Gaucher disease (GD) is an autosomally recessive inherited disorder, caused by mutations of the glucocerebrosidase gene, which codify the enzyme glucocerebrosidase, determining deficiency in its production or activity. The aim of this study was to evaluate the oral health and related quality of life in patients with Gaucher disease, and to evaluate jaw conditions, growth and craniofacial development. Seventeen patients undergoing treatement at the Hematology and Blood Transfusion Center (Hemocentro) of University of Campinas (Unicamp) participated of this study. Eight were children, aged from 7 to 15 years old, and nine adults, aged from 27 to 53 years old. Each patient received a complete soft tissue examination and a clinical examination of decayed, missing and filled primary (dmft) and permanent (DMFT) teeth. Periodontal examination was performed in the adult patients evaluating clinical attachment level (CAL), probing depth (PPD), position of the gingival margin (PGM), visible plaque (VPI) and gingival bleeding index (GBI). Panoramic radiography was used to evaluate the bone conditions of the maxilla and mandible, and the eruption timing of the children's permanent dentition. Lateral radiography was used to evaluate the craniofacial characteristics by cephalometric analysis. Growth was assessed for the children through body weight and height, plotted against standard growth charts; and bone age was estimated by X-ray of the wrist and hand. The influence of the oral health about the quality of life was evaluated by a questionnaire selffilled by the children - Child Perception Questionnaire - CPQ 8-10 years and CPQ 11- 14 years - and the Oral Health Impact Profile questionnaire - OHIP 49 - was used for the adult patients. Wilcoxon test was applied to evaluate the eruption timing of the permanent dentition and to evaluate the values of the cephalometric analysis compared to the standard. The mean dmft found (2.67) was higher, and the DMFT (0.75) was lower than was counseled by the WHO. For the adults, a high DMFT index (20.44) and a slightly gingival and moderate periodontal disease were observed. The children showed growth retardation and a mean difference of 13 months on the first evaluation and of 16 months on the second between the chronologic and bone age. Considering bone age, early eruption was observed in 5 patients, mainly in the central and lateral incisors. Considering chronologic age, 7 patients showed delay eruption, significant for the second premolar. The most prevalent radiological findings in the jaw comprised generalized rarefaction, effacement of the mandibular canal and loss of trabecular structure presented by children and adults. Through the cephalometric analysis all children were observed to present higher values of craniofacial growth confronting with the standards. The mean overall score for the CPQ8-10 years was low (17), showing little impact of the oral health upon quality of life. The mean overall scale for the CPQ11-14 years was 38. According to the results obtained by adults, they perceived substantial impact of oral health upon their quality of life. We concluded that children with GD presented good oral health, early eruption of some permanent teeth groups and important alterations in the jaw. Children may manifest alterations at craniofacial growth. Although the children did not present a poor oral health, some oral conditions interfered with their quality of life. The adult patients showed bone involvement in the jaw and poor oral health, consequently poor oral health-related quality of life. / Doutorado / Odontopediatria / Doutor em Odontologia

Orientador: Eduardo Daruge Júnior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-22T21:09:21Z (GMT). No. of bitstreams: 1 Lima_SilasHenriqueRabelode_M.pdf: 1342549 bytes, checksum: 9f41293af2d63aa8556673b5e61261f2 (MD5) Previous issue date: 2013 / Resumo: A estimativa da idade cronológica (IC) e idade óssea (IO) têm sua importância nos casos forenses e clínicos. O objetivo deste estudo foi comparar a estimativa de idade, obtido pelo desenvolvimento ósseo das vértebras cervicais, em relação à estimativa de idade obtida pelo desenvolvimento ósseo da região da mão e punho, usando três métodos carpais. A amostra foi composta de telerradiografias em norma lateral e radiografias carpais, realizadas na mesma data, de 288 indivíduos, selecionados de um total de 500 inicialmente, pertencentes aos arquivos da Disciplina de Radiologia da Faculdade de Odontologia de Piracicaba - Unicamp (Brasil). A referida amostra constou de 132 indivíduos do sexo feminino, com idade entre 10 e 16 anos, e 156 indivíduos do sexo masculino, com idade entre 11 e 16 anos. As vértebras cervicais foram classificadas segundo os estágios vertebrais (EVs) proposto por Hassel & Farman (1995), de uma forma modificada. Foram analisadas separadamente as bordas inferiores das vértebras cervicais CII, CIII e CIV, obtendo-se a média, e, em seguida, análise dos corpos vertebrais das vértebras CIII e CIV, obtendo-se a média, pelo mesmo método. O estágio vertebral correspondente foi obtido fazendo-se a média entre a média das bordas inferiores e a média dos corpos vertebrais. As radiografias carpais foram analisadas pelos métodos carpais Greulich & Pyle (GP), Tanner et al. (TW3), Eklöf & Ringertz (ER). Foram calculados os coeficientes de correlação intraclasse (ICC) e o coeficiente de correlação de Spearman (SCC). O CCS entre EV e IC foi de rS= 0,9026* e rS = 0,8980* respectivamente, para os sexos feminino e masculino. Os CCS entre EV e os métodos carpais foram de rS = 0,8799*, rS = 0,9113* e rS= 0,8890* respectivamente para ER, GP e TW3, no sexo feminino. Para o sexo masculino obteve-se rS = 0,8988, rS = 0,9327 e rS = 0,9426 para ER, GP e TW3. Conclui-se que a estimativa de IC e IO, avaliando-se os estágios vertebrais, pelo método modificado neste estudo, torna-se confiável na população estudada / Abstract: The estimation of chronological age (CA) and bone age (BA) is quite important in forensic and clinical cases. This study aims to compare the age estimation obtained by the bone development of the cervical vertebrae to that one obtained by the bone development of hand and wrist, by means of three carpal methods. The sample was composed of lateral teleradiographs and carpal radiographs which were at the same date, of 288 individuals that were selected from a total of 500 preselected. The radiographic data files belong to the Department of Dental Radiology of Piracicaba Dental Scholl - University of Campinas (Brazil). The sample consisted of 132 female specimens, of ages varying between 10-16 years-old, and 156 male specimens, varying between 11-16 years-old. The cervical vertebras were classified according to the vertebral stages (VS) proposed by Hassel & Farman (1995), within a modified way. The inferior borders of the cervical vertebras CII, CIII and CIV were separately analyzed, obtaining the average, and then the vertebral bodies of the vertebras CIII and CIV were analyzed in order to obtain the average, by the same method. The corresponding vertebral stage was obtained considering the average between the inferior borders average and vertebral bodies average. The carpal radiographs were analyzed by the carpal method of Greulich & Pyle (GP), Tanner et al (TW3), Eklöf & Ringertz (ER).The intraclass correlation coeficients (ICC) and the Spearman correlation coefficient (SCC) were calculated. The SCC between VS and CA was rS = 0,9026* and rS = 0,8980* respectively, for both male and female specimens. The SCC between VS and carpal methods were rS = 0,8799*, rS = 0,9113* and rS = 0,8890* to ER, GP and TW3, respectively, in female gender specimens. To the male specimens, that was obtained rS = 0,8988, rS = 0,9327 and rS = 0,9426 to ER, GP and TW3, respectively. In conclusion, the age estimation regarding CA and BA, concerning the vertebral stages, by the modified method in this study, becomes reliable within the studied population / Mestrado / Odontologia Legal e Deontologia / Mestre em Biologia Buco-Dental

Abstract Collagen XVIII is a basement membrane proteoglycan, which has three variant N-termini. These variants are coded by two promoters; promoter 1 directs the synthesis of a short variant and promoter 2 directs the synthesis of two longer variants, of which the middle variant is generated from the longest by splicing. The longest variant contains a cysteine-rich domain in its N-terminus, which shows homology to the frizzled receptors of the Wnt molecules and can inhibit Wnt/beta-catenin signalling in vitro. The C-terminal domain of collagen XVIII, endostatin, is an inhibitor of tumor growth and angiogenesis. Lack of collagen XVIII accelerates cutanous wound healing and wound angiogenesis. Overexpression of endostatin leads to delayed wound healing and the presence of morphologically abnormal wound capillaries. Moreover, endostatin overexpression leads to delayed formation of the wound epidermal basement membrane and impaired maturation of hemidesmosomes. Endostatin treatment decreases osteoblast proliferation in vitro. Moreover, osteoblast proliferation and mineralization of the matrix by osteoblasts are inhibited when cells are treated with endostatin together with VEGF. In vivo, lack of collagen XVIII leads to delayed formation of secondary ossification centers in mouse femurs, whereas overexpression of endostatin leads to a slower growth of bone length. However, both of these changes are transient and mild, suggesting that collagen XVIII/endostatin is not essential for skeletal development. The growth of hair follicles is delayed in the mice overexpressing endostatin. This delay in growth is preceded by an impaired hair follicle associated angiogenesis. Lack of collagen XVIII causes an accelerated onset of the first hair cycle. A similar change can be seen in mice lacking the long variants of collagen XVIII. Lack of the short variant causes mild acceleration in the catagen of the first cycle, and anagen is also significantly accelerated in these mice. The long variants were located in the bulge region, which contains the hair follicle stem cells, and in the basement membrane surrounding the dermal papilla. As it is known that several Wnt-inhibitors are upregulated in the bulge, our results suggest that the longest variant of collagen XVIII may have a role as a regulator of Wnt-signalling in hair follicles.

Forelimbs of Day 11 and Day 12 embryonic mice were excised and cultured for 3 d in the presence of either 0.25 μg (8×10-7 M), 0.5 μg(1.7×10-6 M), or 1.0 μg (3.3×10-6 M) of all-rans retinoic acid (RA) per milliliter of culture medium. Cultured limbs were fixed, stained, and mounted whole on glass slides and evaluated with computerized optical image analysis for RA-induced effects on the area and shape of the total limb and individual bone anlagen. Relative effects of RA on total bone, soft tissue, long bone, and paw regions were also examined. With Day 11 forelimbs total bone area was increased by 10.5% by the low dose of RA. The increase was mostly in long bones and at the expense of soft tissue. Total bone area was increased 9.3% with Day 12 forelimbs. This increase was primarily in the paw. The high dose of RA decreased Day 11 forelimb area, primarily affecting long bones. Day 12 forelimbs were not significantly affected by the high dose of RA. Effects of the imtermediate dose were primarily limited to reduction in soft tissue area. Long bone:paw and soft tissue: bone ratios reflected these effects. The high dose produced a consistent rounding or shortening of Day 11 forelimb bones. On Day 12 0.5 μg/ml RA produced an inconsistent pattern of rounding of bone anlagen. Treatment with the high dose on Day 12 produced angular rather than rounded contours in many cases, as indicated by shape factor values closer to zero than obtained with controls. These data show that direct exposure to RA can affect both the size and shape of bone anlagen of the developing limb; the low dose enhances and the high dose depresses development. The results support previous studies which suggest that RA may play a critical role in the control of cell activities such as cell migration, proliferation, and cytodifferentiation in the development of the cartilaginous bone anlagen.

The effect of maternal dietary fats on growth rate and bone development of commercial broilers was examined. Addition of fats [soybean oil (SBO), menhaden oil (MO) and chicken fat (CF)] to the maternal diet altered the tissue and yolk composition of the hens to reflect the dietary fat source. Day-old chick tissues from hens fed MO diet exhibited greater (P ≤0.01) amounts of EPA (20:5n3), DPA (22:5n3), DHA (22:6n3) and total ω-3 fatty acids, and significantly (P ≤0.01) less 20:4n6 than those from hens fed SBO and CF diets. Tissues of day-old chicks from SBO fed hens had larger amounts of 18:2n6, 18:3n3 and total w-6 fatty acids compared to those from CF and MO maternal diets (P ≤ 0.01). These differences disappeared at 4 (WOA) weeks of age. Male and female chicks from the MO maternal diet were lighter (P ≤0.01) during the grow out period than those from CF and SBO diets. Chick tibiae width and diameter from the SBO maternal diet tended to be larger than the MO maternal diet, with significance being noted at d 14 (P ≤ 0.01) and 28 (P ≤ 0.01). Increases (P ≤ 0.01) were observed in shear force and stress required to break chick tibiae from the SBO maternal diet compared to those from the CF and MO maternal diets. The SBO maternal diet stimulates growth rate and bone development and strength of the progeny. / Master of Science

No / Summary We have produced paediatric reference data for forearm sites using the Stratec XCT-2000 peripheral quantitative computed tomography scanner. These data are intended for clinical and research use and will assist in the interpretation of bone mineral density and bone geometric parameters at the distal and mid-shaft radius in children and young adults aged between 6–19 years. Introduction Peripheral quantitative computed tomography (pQCT) provides measurements of bone mineral content (BMC), density (BMD) and bone geometry. There is a lack of reference data available for the interpretation of pQCT measurements in children and young adults. The aim of this study was to provide reference data at the distal and midshaft radius. Methods pQCT was used to measure the 4% and 50% sites of the non-dominant radius in a cohort of healthy white Caucasian children and young adults aged between 5 and 25 years. The lambda, mu, sigma (LMS) technique was used to produce gender-specific reference centile curves and LMS tables for calculating individual standard deviations scores. Results The study population consisted of 629 participants (380 males). Reference centile curves were produced; total and trabecular BMD for age (distal radius) and for age and height, bone area (distal and mid-shaft radius), cortical area, cortical thickness, BMC, axial moment of inertia, stress– strain index and muscle area (mid-shaft radius). Conclusions We present gender-specific databases for the assessment of the distal and mid-shaft radius by pQCT. These data can be used as control data for research studies and allow the clinical interpretation of pQCT measurements in children and young adults by age and height. / Central Manchester and Manchester Children’s University Hospital NHS Research Endowment Fund and the support of the National Osteoporosis Society (Camerton, Bath, UK), which awarded Rebecca Ashby a Linda Edwards Memorial Studentship in 2003 and funded the initial part of the study (1997–1998).

青少年特發性脊柱側凸(Adolescent idiopathic scoliosis , AIS)是一種複雜的脊柱三維畸形，常見於10-16 歲處於生長發育高峰期的青少年女性。儘管AIS 發生率較高並且臨床影響較大，但是到目前為止其病因未明。在眾多關於AIS 病因學的假設和理論研究中，普遍認為低骨密度是AIS 的一個重要影響因素。然而近年來對於AIS 患者低骨密度研究不足，其潛在的機制尚不明確。我們之前初步的組織學研究發現，AIS 患者的松質骨中成骨細胞功能下降，此研究為AIS中存在骨礦化異常提供了初步依據。 / 骨橋蛋白是骨組織中一種重要的非膠原細胞外基質蛋白，其在骨礦化過程中起著重要作用。近期的研究報導AIS 患者血漿中骨橋蛋白水準高於年齡匹配的正常對照。因此本研究假設AIS 患者血漿及骨組織中骨橋蛋白高於正常對照，并可能影響了骨基質的礦化，從而導致低骨密度。 / 本系列研究的第一部分旨在通過外周定量電腦斷層掃描（pQCT）明確AIS患者中皮質骨密度及松質骨密度是否均低於正常對照。pQCT 可以準確地三維評估皮質骨密度，松質骨密度及其他骨品質的相關參數。採用雙能X 線骨密度儀（DXA）測量受試者的非優勢側近端股骨面積骨密度（包括股骨頸，Ward’s 三角及大轉子）。而採用pQCT 測量受試者非優勢側橈骨遠端容積骨密度，包括皮質骨密度及松質骨密度。結果顯示AIS 患者面積骨密度，皮質骨密度及松質骨密度在不同年齡段和月經時間分組中均低於正常對照。並且AIS 與正常對照皮質骨密度的差異隨著年齡增長越來越大，而松質骨密度差異則隨著年齡增長越來越小。 / 第二部分通過顯微CT 及組織形態測定研究AIS 及正常骨組織的骨礦化及骨微結構。採用顯微CT 檢測骨組織的三維結構參數，包括材料骨密度及骨微結構。未脫鈣骨組織的切片通過Goldner’s 染色進行組織形態學測量。結果顯示AIS患者的骨體積分數，骨小梁數目，骨小梁厚度及結構模型指數與正常對照之間均無顯著差異，而材料骨密度顯著低於正常對照。組織形態學分析結果顯示AIS中低礦化骨顯著多於正常對照。 / 第三部分旨在研究AIS 及正常對照血漿中骨橋蛋白水準及其與骨密度的關係。採用酶聯吸附免疫法測量AIS 患者及年齡匹配的正常對照血漿中的骨橋蛋白水準。血漿骨橋蛋白水準與骨密度的關係採用多元回歸分析。研究結果顯示AIS 患者及正常對照血漿骨橋蛋白水平均與年齡及月經時間呈負相關。AIS 患者的血漿骨橋蛋白水準顯著高於正常對照，並且與松質骨密度呈顯著負相關。 / 本研究第四部分旨在探討骨組織中的骨橋蛋白表達與骨形態學及骨礦化指標在AIS 及正常對照中的關係。骨組織中骨橋蛋白的表達採用半定量免疫組織化學法評估。研究結果顯示在AIS 中血漿骨橋蛋白水準與骨組織中骨橋蛋白的表達呈正相關。且AIS 骨組織中骨橋蛋白的表達也顯著高於正常對照。進一步的研究發現骨組織中骨橋蛋白的表達與材料骨密度呈負相關，而與低礦化骨量呈正相關。 / 本研究明確了AIS 中骨礦化水準低於正常對照，進一步證明AIS 患者中的皮質骨及松質骨密度下降可能與骨礦化的調控異常有關。本研究發現的骨橋蛋白與低骨密度及低骨礦化水準的關係，可以推測AIS 患者中異常升高的骨橋蛋白水準可能在骨礦獲取的調解中起重要作用。本系列研究提供證據支援AIS 患者中骨橋蛋白的異常表達可能影響了骨基質的礦化，從而導致低骨密度。本研究為AIS 中低骨密度可能的機制提供了全新的見解，並可能進一步解釋AIS 的發病機理及其發生，發展。 / Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine occurring most commonly in girls between ages 10-16 during the pubertal growth spurt. Despite its high prevalence and clinical impact, etiology of AIS remains largely unknown. Among the number of proposed hypothesis and observations on the etiopathogenesis of AIS, low bone mineral density (BMD) is one of the most reported factor (Cheng et al. 1999; Hung et al. 2005; Cheung et al. 2006; Hui et al. 2011). However, the underlying mechanism of low BMD in AIS has not been sufficiently studied scientifically and its link to the etiopathogenesis is still not clear. From a previous pilot study, our group has reported the histological features of reduced osteoblastic activity in bone biopsy specimens obtained from AIS subjects intraoperatively, thus providing the early evidence of abnormal bone mineral acquisition and mineralization (Cheng et al. 2001). / Osteopontin (OPN) has been recognized as one the major non-collagen extracellular matrix proteins in bone and plays an important role in bone mineralization. Recent report suggested that AIS patients have higher OPN level than normal controls (Moreau et al. 2009). It was hypothesized that the low BMD in AIS is associated with abnormal bone matrix mineralization which may be related to abnormal expression of OPN in the plasma and at tissue level. / In this series of studies, the first part aimed to investigate the differential cortical and trabecular bone mineral density of AIS Vs normal controls. The non-dominant proximal femur areal BMD (aBMD) (femoral neck, Ward’s triangle and greater trochanter) of the subjects were measured with dual-energy x-ray absorptiometry (DXA). The volumetric bone mineral density (vBMD) in non-dominant distal radius was measured with peripheral quantitative computed tomography (pQCT) that allows accurate three dimensional assessment of the cortical and trabecular bone mineral density and other parameters of bone quality. AIS was found to have lower aBMDs, trabecular BMD (TBMD) and cortical BMD (CBMD) in different age groups and year since menarche (YSM) groups. Furthermore, the percentage difference of CBMD between AIS and controls was increased with age while a decreasing trend was observed in the TBMD. / The second part of the study investigated the bone mineralization and bone micro-architecture with micro-computed tomography (micro-CT) and histomorphometry study of bone biopsies obtained from AIS and normal controls. Three-dimensional structural parameters including material bone mineral density (mBMD) and bone architecture were evaluated by micro-CT. Bone histomorphometry was assessed by undecalcified sectioning with Goldner’s trichrome staining. mBMD of trabecular bone in AIS was found to be significantly lower than the normal control while no difference could be demonstrated in BV/TV, Tb.N, Tb.Th and SMI measurement between the two groups. It was also shown that the percentage of low-mineralized bone in AIS was significantly higher than that in normal controls. / The third part aimed to study the plasma OPN level and its association with the BMD in AIS Vs normal controls. Plasma OPN level in AIS and age-matched controls was measured by ELISA. With multivariate regression analysis, the plasma OPN level was found to be negatively correlated with Age and YSM in both AIS and normal controls. In addition, the plasma OPN level in AIS was significantly higher and correlated with the low trabecular BMD. / The fourth part of the study investigated the OPN expression in bone tissues level and its association with histomorphometric bone mineralization and bone micro-architectural parameters in AIS Vs normal controls. OPN expression in bone biopsy was semi-quantified by immunohistochemistry. It was found that the bone tissue OPN level was significantly higher in AIS and also positively correlated with plasma OPN level. In addition, in this pilot study, we found the trend that OPN expression in trabecular bone was negatively associated with mBMD, and positively with the percentage of low-mineralized bone. / The present study showed that AIS had lower bone mineralization than normal controls. The low cortical and trabecular BMD found in AIS is likely to be resulting from abnormal regulation of bone mineralization. The association of OPN with abnormal BMD and bone mineralization further suggested that abnormal OPN level might play an important role in affecting the bone mineral acquisition in AIS. All of these findings strongly supported the hypothesis that the low BMD in AIS is associated with abnormal bone matrix mineralization which could be related to abnormal expression of OPN. This study provided important additional insight into the possible mechanism of lower bone mineral density that might be linked to theetiopathogenesis, development and progression of the spinal deformity in AIS. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Sun, Guangquan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 143-160). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract and appendix A also in Chinese. / THE CHINESE UNIVERSITY OF HONG KONG --- p.I / ACKNOWLEDGEMENTS --- p.II / ABSTRACT --- p.IV / ABBREVIATION --- p.XI / TABLE OF CONTENTS --- p.XIII / LIST OF TABLES --- p.XVII / LIST OF FIGURES --- p.XIX / LIST OF PUBLICATIONS --- p.XXI / Chapter CHAPTER 1 --- STUDY BACKGROUND --- p.1 / Chapter 1.1 --- GENERAL OVERVIEW OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS) --- p.2 / Chapter 1.1.1 --- NATURAL HISTORY --- p.4 / Chapter 1.1.2 --- CURRENT TREATMENTS --- p.6 / Chapter 1.1.2.1 --- Observation --- p.7 / Chapter 1.1.2.2 --- Bracing --- p.7 / Chapter 1.1.2.3 --- Surgical treatments --- p.9 / Chapter 1.1.3 --- CURRENT HYPOTHESIS ON THE ETIOLOGY OF AIS --- p.11 / Chapter 1.1.3.1 --- Genetic factors --- p.12 / Chapter 1.1.3.2 --- Neuromuscular impairment --- p.14 / Chapter 1.1.3.3 --- Abnormalities in skeletal development --- p.16 / Chapter 1.1.3.4 --- Low bone mineral density in AIS --- p.16 / Chapter 1.2 --- BONE MINERALIZATION --- p.18 / Chapter 1.2.1 --- Overview of bone mineralization --- p.18 / Chapter 1.2.2 --- Bone modeling --- p.18 / Chapter 1.2.3 --- Bone remodeling --- p.19 / Chapter 1.2.4 --- Factors affecting bone mineralization --- p.21 / Chapter 1.3 --- OSTEOPONTIN --- p.23 / Chapter 1.3.1 --- Structure of osteopontin --- p.23 / Chapter 1.3.2 --- Osteopontin - cellular and tissue distribution --- p.24 / Chapter 1.3.3 --- Osteopontin functions --- p.25 / Chapter 1.3.4 --- Osteopontin functions in bone --- p.25 / Chapter 1.3.5 --- Osteopontin and bone mineral density in human --- p.29 / Chapter CHAPTER 2 --- STUDY HYPOTHESIS AND PLAN --- p.31 / Chapter 2.1 --- INTRODUCTION --- p.32 / Chapter 2.2 --- HYPOTHESIS --- p.33 / Chapter 2.3 --- OBJECTIVES --- p.34 / Chapter 2.4 --- STUDY PLAN --- p.34 / Chapter CHAPTER 3 --- LOW BONE MINERAL DENSITY IN ADOLESCENT IDIOPATHIC SCOLIOSIS - AREAL VS VOLUMETRIC, CORTICAL VS TRABECULAR BONE MINERAL DENSITY --- p.36 / Chapter 3.1 --- INTRODUCTION --- p.37 / Chapter 3.2 --- SUBJECTS AND METHODS --- p.39 / Chapter 3.2.1 --- Subjects --- p.39 / Chapter 3.2.2 --- BMD Measurement --- p.40 / Chapter 3.2.3 --- Statistical Analysis --- p.41 / Chapter 3.3 --- RESULTS --- p.42 / Chapter 3.3.1 --- aBMD of AIS and normal controls by age groups --- p.42 / Chapter 3.3.2 --- TBMD and CBMD in AIS and normal controls by age groups --- p.42 / Chapter 3.3.3 --- aBMD in AIS and normal controls by year since menarche --- p.43 / Chapter 3.3.4 --- TBMD and CBMD in AIS and normal controls by year since menarche --- p.43 / Chapter 3.3.5 --- Correlation between CBMD & TBMD and chronological age or year since menarche --- p.44 / Chapter 3.3.6 --- Comparisons adjusted for chronological age or year since menarche --- p.44 / Chapter 3.4 --- DISCUSSION --- p.45 / Chapter 3.5 --- TABLES AND FIGURES --- p.50 / Chapter CHAPTER 4 --- ABNORMAL BONE MATRIX MINERALIZATION AND BONE MICROARCHITECTURE IN ADOLESCENT IDIOPATHIC SCOLIOSIS - A HISTOMORPHOMETRIC AND MICRO-CT STUDY --- p.60 / Chapter 4.1 --- INTRODUCTION --- p.61 / Chapter 4.2 --- SUBJECTS AND METHODS --- p.62 / Chapter 4.2.1 --- Subjects --- p.62 / Chapter 4.2.2 --- Micro-computed tomography --- p.63 / Chapter 4.2.3 --- Bone histomorphometry --- p.64 / Chapter 4.2.4 --- Statistical analysis --- p.68 / Chapter 4.3 --- RESULTS --- p.68 / Chapter 4.3.1 --- Results of micro-CT analysis --- p.68 / Chapter 4.3.2 --- Results of histomorphometric analysis --- p.69 / Chapter 4.3.3 --- Relationship of mBMD and percentage of low-mineralized bone --- p.69 / Chapter 4.4 --- DISCUSSION --- p.70 / Chapter 4.5 --- TABLES AND FIGURES --- p.74 / Chapter CHAPTER 5 --- PLASMA OSTEOPONTIN LEVEL AND ITS ASSOCIATION WITH BONE MINERAL DENSITY IN ADOLESCENT IDIOPATHIC SCOLIOSIS --- p.82 / Chapter 5.1 --- INTRODUCTION --- p.83 / Chapter 5.2 --- SUBJECTS AND METHODS --- p.84 / Chapter 5.2.1 --- Subjects --- p.84 / Chapter 5.2.2 --- Anthropometric assessment --- p.84 / Chapter 5.2.3 --- Plasma osteopontin measurement --- p.85 / Chapter 5.2.4 --- BMD Measurement --- p.86 / Chapter 5.2.5 --- Statistical Analysis --- p.86 / Chapter 5.3 --- RESULTS --- p.86 / Chapter 5.3.1 --- Comparison of anthropometric parameters between AIS and controls --- p.86 / Chapter 5.3.2 --- Correlation between OPN plasma level with age or YSM in AIS and controls --- p.87 / Chapter 5.3.3 --- Comparison of OPN plasma level between AIS and controls --- p.87 / Chapter 5.3.4 --- Correlation between OPN plasma level and curve severity in AIS --- p.87 / Chapter 5.3.5 --- Relationship between OPN plasma level and vBMD --- p.88 / Chapter 5.4 --- DISCUSSION --- p.88 / Chapter 5.5 --- TABLES AND FIGURES --- p.94 / Chapter CHAPTER 6 --- OSTEOPONTIN EXPRESSION IN BONE TISSUE AND ITS ASSOCIATION WITH BONE MATRIX MINERALIZATION IN ADOLESCENT IDIOPATHIC SCOLIOSIS - A PILOT STUDY --- p.102 / Chapter 6.1 --- INTRODUCTION --- p.103 / Chapter 6.2 --- SUBJECTS AND METHODS --- p.104 / Chapter 6.2.1 --- Subjects --- p.104 / Chapter 6.2.2 --- Micro-computed tomography --- p.104 / Chapter 6.2.3 --- Bone histomorphometry --- p.104 / Chapter 6.2.4 --- Semi-quantification of OPN expression in bone biopsy by immunohistochemistry --- p.105 / Chapter 6.2.5 --- Plasma osteopontin measurement --- p.107 / Chapter 6.2.6 --- Statistical Analysis --- p.108 / Chapter 6.3 --- RESULTS --- p.108 / Chapter 6.3.1 --- Comparison of anthropometric parameters between AIS and control subjects --- p.108 / Chapter 6.3.2 --- Comparison of OPN expression detected by immunohistochemistry in bone biopsy between AIS and control groups --- p.108 / Chapter 6.3.3 --- Comparison of histomorphometric and micro-CT results between AIS and control groups --- p.109 / Chapter 6.3.4 --- Relationship between plasma OPN level and OPN expression in bone biopsy --- p.109 / Chapter 6.3.5 --- Relationship between percentage of low-mineralized bone and OPN expression in bone biopsy --- p.109 / Chapter 6.3.6 --- Relationship between material bone mineral density and OPN expression in bone biopsy --- p.110 / Chapter 6.4 --- DISCUSSION --- p.110 / Chapter 6.5 --- TABLES AND FIGURES --- p.114 / Chapter CHAPTER 7 --- SUMMARY STUDY FLOWCHART, OVERALL DISCUSSION, CONCLUSIONS, LIMITATIONS AND FURTHER STUDIES --- p.119 / Chapter 7.1 --- SUMMARY OF THE STUDY FLOW CHART WITH KEY FINDINGS --- p.120 / Chapter 7.2 --- OVERALL DISCUSSION --- p.125 / Chapter 7.2.1 --- The novel findings on bone mineralization abnormality in AIS in this study --- p.125 / Chapter 7.2.2 --- OPN is a key modulator in AIS --- p.128 / Chapter 7.3 --- OVERALL CONCLUSIONS --- p.130 / Chapter 7.4 --- LIMITATION OF THIS STUDY AND FUTURE RESEARCH --- p.131 / Chapter APPENDIX A. --- CONSENT FORM OF AIS RESEARCH --- p.135 / Chapter APPENDIX B. --- CONSENT FORM OF BONE BIOPSY COLLECTION --- p.137 / Chapter APPENDIX C. --- MATERIALS AND REAGENTS INFORMATION AND PROTOCOL FOR SOLUTIONS PREPARATION --- p.138 / BIBLIOGRAPHY --- p.143

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed on Feb. 19, 2010). Includes bibliographical references.

The role of Indian hedgehog (Ihh) signalling in the regulation of endochondral bone formation is well established. Ihh controls the rate of bone growth by negatively regulating differentiation and positively regulating growth plate chondrocyte proliferation. It has been well documented also that mutations resulting in constitutive activation of signalling through FGFR3 in chondrodysplasia, lead to a significant decrease in this important signalling factor accompanied by reduced proliferation of the chondrocytes and a dwarf phenotype. / In an attempt to rescue the chondrodysplasia phenotype hedgehog agonist Hh-Ag 1.4 was injected subcutaneously into mice with achondroplasia (ACH) or with severe achondroplasia with developmental delay and acanthosis negricans (SADDAN) with mixed results. / Administration of a hedgehog agonist in SADDAN mice led to a significant up-regulation of both Ptch and Gli1, as measured by quantitative PCR, indicating that Hh-Ag 1.4 does indeed stimulate hedgehog signalling in vivo. Also, in situ hybridization for Ihh seems to show a down regulation of native Ihh expression in pre-hypertrophic chondrocytes, possibly due to the activation of the negative PTHrP feedback loop. In our study, Hh-Ag 1.4 treatment resulted in an increased growth plate length and reduced size of the hypertrophic zone. The cortical bone flanking the growth plate in mice injected with Hh-Ag 1.4 was 2-3 times thicker than in control mice, which may be attributed to the positive effect of increased Ihh signalling in osteoblastogenesis. Contrary to our expectations, there was also a noticeable reduction in chondrocyte proliferation in mice treated with the agonist. / Overall, the effect on the growth of long bones was not beneficial and the treatment with high doses of Hh-Ag 1.4 did not result in an amelioration of the chondrodysplastic phenotype.

Vitamin D is important for bone development with immunomodulatory effects. This study investigated whether feeding CD-1 and interleukin 10 (IL-10) knockout (KO) dams low (25 IU/kg diet) or high (5,000 IU/kg diet) vitamin D affected bone health of dams as well as their offspring. Offspring were weaned to 1 of the 2 diets and followed to young adulthood. Unlike CD-1 dams, IL-10 KO dams experienced greater femur strength with high vitamin D. CD-1 male offspring had reduced femur neck strength and female offspring had smaller, weaker femurs, and weaker lumbar vertebra 2 (LV2) with high maternal vitamin D. IL-10 KO male offspring had larger femurs and female offspring had stronger femurs when weaned to high vitamin D. Low vitamin D did not adversely impact bone health but the optimal level of dietary vitamin D seems to differ between healthy and inflammatory states.