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首页> 外文学位 >The Relationship of Leptin and Leptin Bioavailability with Body Composition, Bone Quality and Osteoblast Functions in Adolescent Idiopathic Scoliosis.
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The Relationship of Leptin and Leptin Bioavailability with Body Composition, Bone Quality and Osteoblast Functions in Adolescent Idiopathic Scoliosis.

机译：瘦素和瘦素生物利用度与青少年特发性脊柱侧弯患者身体成分，骨质量和成骨细胞功能的关系。

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Introduction: Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional structural deformity of the spine and its etiology remains unknown. It mainly occurs in girls between 11 to 14 years old with a prevalence rate of 4%. This common spinal deformity can be associated with significant cosmetic, psychological, and clinical morbidities in severe cases. Current treatments for AIS are unsatisfactory, mainly because they are merely treating the phenotype of the spinal deformity but not the underlying etiology. Therefore, it is crucial to understand the etiopathogenesis of AIS so that effective therapeutic and preventive measures can be devised.;Previous studies have reported the association between AIS and low body weight, tall stature, increased arm span, low body mass index, delayed onset of menarche and low bone mass, which indicated abnormal systemic growth in patients with AIS. Leptin has been postulated as one of the etiologic factors of AIS because of its important physiological functions in neuro-osseous development affecting skeletal growth, the onset of puberty, energy expenditure and body composition. A previous study had reported lower circulating leptin in AIS girls than age- and sex-matched controls. However, the strength of leptin signal is not only determined by the leptin level, it could also be affected by soluble leptin receptor (sOB-R), its binding protein in circulation. sOB-R could modulate the serum leptin level, and affect the bioavailability of free leptin, the biologically active form, to its target tissues. Free leptin index (FLI) was developed to aid interpretation of data and provide an estimation of free leptin level.;The effects of leptin on bone metabolism are exerted indirectly through the central nervous system and directly on the peripheral tissues. Leptin was shown to have a catabolic effect on bone formation through the hypothalamus and the sympathetic nervous system (SNS). While the peripheral effects of leptin was shown to be anabolic to bone formation, promoting the proliferation of osteoblasts and chondrocytes, stimulating osteoblastic differentiation, mineralization, and inhibiting osteoclastogenesis and osteoclast activity. With regards to AIS, a previous study on bone marrow derived mesenchymal stem cells (MSCs) showed lower responses to leptin, and lower leptin receptor expressions in adipogenic and osteogenic MSCs. This study provided initial evidence that leptin related pathways might be abnormal in the bone cells of AIS patients.;This study aimed to: 1) Investigate if there is any abnormality in free leptin bioavailability by measuring the serum total leptin, sOB-R levels, and FLI in AIS and control subjects, and if it is associated with abnormal anthropometric parameters in AIS. 2) Investigate if free leptin bioavailability in AIS is associated with abnormal body composition by studying the difference in body composition and its correlations with serum total leptin, sOB-R, and FLI between AIS and control subjects. 3) Investigate if free leptin bioavailability in AIS is associated with abnormal bone quality by studying the difference in bone quality as measured by high resolution pQCT and its correlations with serum total leptin, sOB-R, and FLI between AIS and control subjects. 4) Investigate if there are abnormal functional responses to leptin and abnormal expression of leptin receptor in AIS by determining the effects of leptin on proliferation, differentiation, and mineralization of osteoblasts; and the expression levels of leptin receptor in osteoblasts isolated from intra-operative bone biopsies of AIS and control subjects.;Methods: 1) The study on free leptin bioavailability and anthropometric parameters included 207 AIS girls and 155 age- and gender-matched normal controls. Subjects with body mass index (BMI)>23.0 were excluded to avoid bias from the relatively high serum leptin level in overweight / obese subjects. Assessments included anthropometric and sexual maturity measurements: body weight, height, arm span, sitting height, BMI, and Tanner stages. Serum total leptin and sOB-R levels were measured with ELISA, and free leptin index (FLI) was calculated as the ratio of serum total leptin / sOB-R. 2) The study on free leptin bioavailability and body composition included 148 AIS girls and 116 normal controls, while anthropometric and sexual maturity parameters included 207 AIS girls and 155 normal controls. Body composition was assessed with bioelectrical impedance analysis (BIA). 3) The study on free leptin bioavailability and bone quality parameters included 207 AIS girls and 155 normal controls. Bone quality on the non-dominant distal radius was assessed with high resolution pQCT (HR-pQCT). In vivo bone strength was assessed with finite element analysis (FEA). 4) The study on functional responses and leptin receptor expression in osteoblasts included 12 AIS girls undergoing corrective spinal surgery and 6 control subjects undergoing unrelated surgery. Primary osteoblasts were isolated from intra-operative bone biopsies, and were cultured and assessed for the effects of leptin (0, 10, 100, 1000 ng/mL) on cell proliferation, differentiation, and mineralization by MTT assay, alkaline phosphatase activity assay and osteocalcin ELISA, and von Kossa staining respectively. Protein expressions of leptin receptor (LEP-R) under basal and osteogenic conditions were compared between AIS and controls by Western blot.;Results: 1) In the study on free leptin bioavailability and anthropometric parameters, AIS girls had higher sOB-R and lower FLI after adjusting for age and body weight, and these were associated with lower body weight and lower BMI. Significant correlation between serum total leptin and sOB-R was found in controls, but no correlation was observed in AIS girls. AIS girls also showed markedly weaker correlations between serum total leptin, FLI, and anthropometric parameters. 2) In the study on free leptin bioavailability and body composition, AIS girls had lower skeletal muscle mass, lower body fat, and percentage body fat, as well as weaker correlations between serum total leptin, FLI, and all body composition parameters. 3) In the study on free leptin bioavailability and bone quality, AIS girls had lower cortical volumetric bone mineral density (vBMD), lower trabecular number, higher trabecular separation, and higher structural model index (SMI) value. In correlation analysis with serum total leptin and FLI, AIS girls had distinctive correlation pattern with trabecular bone parameters that was not observed in the normal controls. 4) In the study on functional responses and leptin receptor expression in osteoblasts, control group showed increasing MTT signals to leptin in a dose dependent manner, while AIS group showed no proliferative response to leptin. For differentiation, control group showed strong and significant trend in ALP activity to increasing leptin concentrations in both day 6 and 14, but this trend was not observed in the AIS group. Osteoblasts from the control group secreted osteocalcin in an increasing dose dependent manner to leptin, but AIS group showed weak responses to leptin. For mineralization, the control group showed a mild increasing trend to increasing leptin concentrations, and again no trend was observed in the AIS group. No significant differences in the expression of leptin receptor under basal and osteogenic conditions were found between AIS and control group.;Discussion: This is the first study on the relationship of leptin bioavailability with body composition and bone quality in AIS. The results in this study suggested that abnormal free leptin bioavailability might exist in AIS girls and could lead to abnormal phenotypes such as lower BMI, abnormal body composition, and deranged bone quality that often manifested in AIS simultaneously. The importance of low bone mass in AIS and the presence of correlations between trabecular bone parameters and serum total leptin and FLI which were not observed in controls, have led us to further investigate the effects of leptin on primary osteoblasts in AIS. The osteoblasts isolated from AIS girls had no or very low response to leptin when compared with controls, which was shown to be independent of the difference in leptin receptor expression levels. This lack of response might be due to dysfunction of leptin signaling pathway, which might include structural or binding abnormalities in the leptin receptor or downstream signal molecules. This is an important finding and might serve to explain the low bone mass and deranged bone quality that is associated with AIS. This study provided new insights and new research directions on the etiopathogenesis of AIS. Future research could include studies on the downstream signal molecules along the leptin pathways that might be affected in AIS, and animal models to confirm the causal relationship of leptin and leptin bioavailability to AIS. In summary, the findings in this series of studies demonstrated the importance of leptin and leptin bioavailability in skeletal growth, body build, bone quality, and the etiopathogenesis of AIS.
机译：简介：青少年特发性脊柱侧凸（AIS）是脊柱的复杂三维结构畸形，其病因仍未知。它主要发生在11至14岁之间的女孩中，患病率为4％。在严重的情况下，这种常见的脊柱畸形可能与明显的美容，心理和临床发病率相关。目前对AIS的治疗并不令人满意，主要是因为它们仅治疗脊柱畸形的表型而不是潜在的病因。因此，了解AIS的病因是至关重要的，以便制定有效的治疗和预防措施。;先前的研究已经报道了AIS与体重低，身材高大，臂展增加，体重指数低，发病延迟有关月经初潮和低骨量，表明AIS患者全身生长异常。瘦素被认为是AIS的病因之一，因为它在影响骨骼生长，青春期发作，能量消耗和身体组成的神经骨发育中具有重要的生理功能。先前的一项研究报道，AIS女孩的循环瘦素低于年龄和性别匹配的对照组。然而，瘦素信号的强度不仅取决于瘦素水平，还可能受可溶性瘦素受体（sOB-R）（其在循环中的结合蛋白）的影响。 sOB-R可以调节血清瘦素水平，并影响游离瘦素（其生物活性形式）对其靶组织的生物利用度。建立了游离瘦素指数（FLI）以帮助解释数据并提供游离瘦素水平的估计。瘦素对骨代谢的影响通过中枢神经系统间接作用，并直接作用于周围组织。瘦素被证明对下丘脑和交感神经系统（SNS）的骨形成有分解代谢作用。瘦素的外周作用显示出对骨形成的合成代谢没有影响，可促进成骨细胞和软骨细胞的增殖，刺激成骨细胞分化，矿化并抑制破骨细胞和破骨细胞活性。关于AIS，先前对骨髓来源的间充质干细胞（MSC）的研究显示，脂肪形成和成骨MSC对瘦素的反应较低，瘦素受体的表达较低。这项研究提供了初步的证据，表明AIS患者的骨细胞中瘦素相关途径可能异常。该研究旨在：1）通过测量血清总瘦素，sOB-R水平调查游离瘦素的生物利用度是否存在异常，以及AIS和对照组的FLI，以及是否与AIS中异常的人体测量学参数有关。 2）通过研究AIS与对照组之间的身体组成差异及其与血清总瘦素，sOB-R和FLI的相关性，研究AIS中游离瘦素的生物利用度是否与异常的身体组成有关。 3）通过研究高分辨率pQCT测量的骨骼质量差异及其与AIS与对照组之间血清总瘦素，sOB-R和FLI的相关性，研究AIS中游离瘦素的生物利用度是否与异常骨骼质量相关。 4）通过确定瘦素对成骨细胞增殖，分化和矿化的影响，调查AIS中对瘦素的功能反应是否异常以及瘦素受体的表达是否异常；方法：1）207名AIS女孩和155名年龄和性别相匹配的正常对照研究游离瘦素的生物利用度和人体测量学参数。 。体重指数（BMI）> 23.0的受试者被排除在外，以避免超重/肥胖受试者中相对较高的血清瘦素水平产生偏差。评估包括人体测量和性成熟度测量：体重，身高，臂展，坐姿高度，BMI和Tanner阶段。用ELISA测量血清总瘦素和sOB-R水平，并以血清总瘦素/ sOB-R之比计算游离瘦素指数（FLI）。 2）游离瘦素的生物利用度和身体组成的研究包括148名AIS女孩和116名正常对照，而人体测量学和性成熟度参数包括207名AIS女孩和155名正常对照。身体成分通过生物电阻抗分析（BIA）进行评估。 3）游离瘦素的生物利用度和骨质量参数的研究包括207名AIS女孩和155名正常对照。非高分辨率远端radius骨的骨质量通过高分辨率pQCT（HR-pQCT）进行评估。使用有限元分析（FEA）评估体内骨骼强度。 4）对成骨细胞功能反应和瘦素受体表达的研究包括12名接受矫正脊柱外科手术的AIS女孩和6名接受无关手术的对照组。从术中骨活检组织中分离出原代成骨细胞，进行培养并通过MTT分析，碱性磷酸酶活性分析和LPT评估瘦素（0、10、100、1000 ng / mL）对细胞增殖，分化和矿化的影响。骨钙素ELISA和von Kossa染色。通过蛋白质印迹比较了AIS和正常人在基础和成骨条件下瘦素受体（LEP-R）的蛋白表达。结果：1）在自由瘦素的生物利用度和人体测量学参数研究中，AIS女孩的sOB-R较高而较低。调整年龄和体重后的FLI，这些与体重减轻和BMI降低有关。在对照组中发现血清总瘦素与sOB-R之间存在显着相关性，但在AIS女孩中未观察到相关性。 AIS女孩还显示血清总瘦素，FLI和人体测量学参数之间的相关性明显弱。 2）在关于游离瘦素生物利用度和身体成分的研究中，AIS女孩的骨骼肌质量较低，身体脂肪含量和体脂百分比较低，并且血清总瘦素，FLI和所有身体成分参数之间的相关性较弱。 3）在对游离瘦素的生物利用度和骨质量的研究中，AIS女孩的皮质体积骨矿物质密度（vBMD）较低，小梁数目较低，小梁分离度较高，结构模型指数（SMI）较高。在与血清总瘦素和FLI的相关性分析中，AIS女孩与小梁骨参数具有独特的相关性模式，而正常对照组中没有观察到。 4）在成骨细胞功能反应和瘦素受体表达的研究中，对照组对瘦素的MTT信号呈剂量依赖性增加，而AIS组对瘦素无增殖反应。为了进行区分，对照组在第6天和第14天均显示出ALP活性强于瘦素浓度升高的强烈趋势，但在AIS组中未观察到这种趋势。对照组的成骨细胞对瘦素的分泌呈剂量依赖性增加，但AIS组对瘦素的反应较弱。对于矿化，对照组显示出瘦素浓度逐渐增加的趋势，而在AIS组中也未观察到趋势。 AIS与对照组在基础和成骨条件下瘦素受体的表达差异均无统计学意义。讨论：这是AIS中瘦素生物利用度与人体成分和骨质量关系的首次研究。这项研究的结果表明，AIS女孩体内可能存在异常的游离瘦素生物利用度，并可能导致异常的表型，例如BMI降低，身体组成异常以及经常在AIS中表现出来的骨骼质量异常。低骨量在AIS中的重要性以及在对照中未观察到的小梁骨参数与血清总瘦素和FLI之间的相关性使我们进一步研究了瘦素对AIS中原代成骨细胞的影响。与对照组相比，从AIS女孩中分离出的成骨细胞对瘦素的反应没有或非常低，这表明与瘦素受体表达水平的差异无关。这种缺乏响应可能是由于瘦素信号传导途径的功能障碍，可能包括瘦素受体或下游信号分子的结构或结合异常。这是一个重要发现，可能有助于解释与AIS相关的骨质低和骨骼质量异常。该研究为AIS的发病机制提供了新的见解和新的研究方向。未来的研究可能包括研究可能在AIS中影响瘦素途径的下游信号分子，以及确定瘦素和瘦素生物利用度与AIS因果关系的动物模型。总而言之，这一系列研究的结果证明了瘦素和瘦素的生物利用度在AIS的骨骼生长，体质，骨质和病因中的重要性。

著录项

  • 作者

    Tam, Man Shan Elisa.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Public health.;Pathology.;Endocrinology.;Physiology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 341 p.
  • 总页数 341
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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