Estrogen Effect on Beak Ligament Structure-Function Relationship in Thumb Basal Joint

雌激素对拇指基底关节喙韧带结构与功能关系的影响

• 批准号: 10244925
• 负责人: Yongren Wu
• 金额: $ 23.45万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244925
• 关键词: Affect; Beak; Biochemical; Biological; Centers of Research Excellence; Classification; Complex; Data; Degenerative polyarthritis; Diagnosis; Early Diagnosis; Environment; Estradiol; Estrogen Receptors; Estrogens; Etiology; Female; Future; Goals; Health; Homeostasis; In Vitro; Joint Instability; Joint repair; Joints; Knowledge; Ligaments; Mechanics; Mediating; Menopause; Morphology; Muscle; Musculoskeletal; Pathologic; Patients; Pattern; Postmenopause; Procedures; Research; Secondary to; Site; Structure; Structure-Activity Relationship; Surface; System; Thumb structure; Tissues; Translational Research; Upper Extremity; Validation; Woman; cohort; female sex hormone; human female; human subject; improved; in vivo; kinematics; men; pathomechanics; preservation; receptor expression; soft tissue; virtual human; virtual model

The trapeziometacarpal (TMC) joint is the most common site of disabling osteoarthritis (OA) in the upper limb and has a strong predilection for postmenopausal women. The ratio of women to men for basal joint reconstructive procedures for OA is 10-20:1. Structurally, the TMC joint is a complex biconcave saddle- shaped joint with limited bony constraint. While muscles provide the active dynamic stabilization of the joint, surrounding ligaments are the major static stabilizers of the joint. Previous pathologic studies suggest a potential etiologic relationship between the beak ligament (primary TMC stabilizing ligament) degeneration and the TMC OA. Despite extensive pathophysiologic studies in TMC joint, the TMC OA mechanism with 10-20 fold increase in postmenopausal women remains unclear. Estrogen, the primary female sex hormone that significantly diminishes after menopause, has been found to interfere with the soft tissue homeostasis. We hypothesize that primary attritional changes in the beak ligament insertions mediated by estrogen receptors (ER a&b), affect the structural integrity and kinematic function of the beak ligament. Joint instability secondary to the beak ligament attrition is suspected to further change the local TMC mechanical environment which may initiate/accelerate the TMC OA progression in postmenopausal females. To validate the hypothesis, we aim to: 1) in vitro study: determine the localized morphological, mechanoelectrical, and biochemical changes of the beak ligament in relation to estrogen receptor expression and tissue bound estradiol levels; 2) in vitro study: develop a musculoskeletal function assessment system to determine the impact of beak ligament laxity/detachment on TMC kinematics and local joint environment; 3) in vivo validation: validate the morphometric patterns and kinematic function of the beak ligament in a cohort of female human subjects at various OA stages. Successful completion of this proposal will fill the knowledge gap with robust data regarding negative impact of estrogen deficiency on beak ligament integrity and kinematic function in postmenopausal females. It will support further understanding the biological and mechanical factors interaction on beak ligament integrity and function in our future larger scale study. This project intends to shift the current TMC pathomechanics research paradigm from articulating surface to surrounding beak ligament toward our long-term goals regarding early diagnosis and management of OA - a complementary ligament morphometric grading and a TMC kinematic classification system will be introduced for OA diagnosis in addition to the commonly used Eaton-Littler classification system; it will lead to a local TMC OA management strategy focusing on beak ligament insertion preservation. Integrating both experimental and numeri IMH focus of patient-specific modeling for "virtual human trials".

腕掌（TMC）关节是上肢致残性骨关节炎（OA）最常见的部位，且在绝经后妇女中具有强烈的偏好。接受骨性关节炎基底关节重建手术的女性与男性的比例为10-20：1。在结构上，TMC关节是一个复杂的双凹面鞍形关节，具有有限的骨性限制。虽然肌肉提供关节的主动动态稳定，但周围韧带是关节的主要静态稳定器。先前的病理学研究表明喙韧带（原发性TMC稳定韧带）变性和TMC OA之间存在潜在的病因学关系。尽管对TMC关节进行了广泛的病理生理学研究，但绝经后妇女TMC OA增加10-20倍的机制仍不清楚。雌激素，主要的女性性激素，绝经后显着减少，已被发现干扰软组织的稳态。我们假设，在喙韧带插入的雌激素受体（ER a&B）介导的主要attrition变化，影响喙韧带的结构完整性和运动功能。怀疑继发于喙韧带磨损的关节不稳定进一步改变了局部TMC机械环境，这可能引发/加速绝经后女性的TMC OA进展。为了验证这一假设，我们的目标是：1）体外研究：确定与雌激素受体表达和组织结合雌二醇水平相关的喙韧带的局部形态学、机械电和生化变化; 2）体外研究：开发肌肉骨骼功能评估系统，以确定喙韧带松弛/脱离对TMC运动学和局部关节环境的影响; 3）体内验证：验证在不同OA阶段的一组女性人类受试者中喙韧带的形态学模式和运动学功能。成功完成这一提案将填补知识空白与强大的数据，雌激素缺乏对喙韧带完整性和运动功能的负面影响，在绝经后女性。这将有助于进一步了解生物和力学因素的相互作用对喙韧带的完整性和功能，在我们未来的更大规模的研究。本项目旨在将目前TMC病理力学研究范式从关节面转向周围喙韧带，以实现我们关于OA早期诊断和管理的长期目标-除了常用的Eaton-Littler分类系统外，还将引入补充韧带形态测量分级和TMC运动学分类系统用于OA诊断;这将导致一个本地TMC OA管理策略，重点是喙韧带附着保留。整合实验和数字IMH的重点患者特定的建模“虚拟人体试验”。