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

斜方掌骨(TMC)关节是上肢最常见的致残性骨关节炎(OA)部位，对绝经后女性有很强的偏好。骨性关节炎基础关节重建术的男女比例为10-20：1。TMC关节在结构上是一个复杂的双凹鞍形关节，具有有限的骨约束。肌肉为关节提供主动的动态稳定，而周围的韧带是关节的主要静态稳定器。以前的病理学研究表明，喙韧带(初级TMC稳定韧带)退变与TMC OA之间存在潜在的病因关系。尽管对TMC关节进行了广泛的病理生理学研究，但绝经后女性TMC OA增加10-20倍的机制仍不清楚。雌激素是绝经后显著减少的主要女性性激素，已被发现会干扰软组织的动态平衡。我们假设，由雌激素受体(ERa和ERb)介导的喙韧带附着点的主要磨损改变，影响喙韧带的结构完整性和运动功能。继发于喙韧带磨损的关节不稳定可能进一步改变了局部TMC的力学环境，从而可能启动/加速绝经后女性TMC OA的进展。为了验证这一假说，我们的目标是：1)体外研究：确定喙韧带局部的形态、力电和生化变化与雌激素受体表达和组织结合雌二醇水平的关系；2)体外研究：建立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：验证不同阶段女性受试者喙韧带的形态计量学模式和运动功能。这项建议的成功完成将用有关雌激素缺乏对绝经后女性喙韧带完整性和运动功能的负面影响的可靠数据填补这一知识空白。这将为我们今后更大规模的研究进一步了解生物和力学因素对喙韧带完整性和功能的影响提供支持。本项目旨在将目前的TMC病理力学研究范式从关节表面转移到周围喙韧带，朝着我们关于OA早期诊断和治疗的长期目标-在常用的Eaton-Littler分类系统的基础上，引入补充韧带形态计量学分级和TMC运动学分类系统用于OA诊断；这将导致局部TMC OA的管理策略，重点放在喙韧带插入保存上。将实验和数值两个方面的重点结合起来，为“虚拟人试验”建立特定于患者的模型。

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".