Role and underlying mechanisms of integrin α2β1 related cell-matrix interaction in tendon homeostasis and age related degradation

衰老影响解剖学和生理学的多个方面，包括连接肌肉和骨骼的肌腱。它降低了肌腱的新陈代谢活性和组织再生能力。肌腱中与年龄相关的结构变化，如胶原含量的减少，降低了肌腱的力学性能，使其易于受伤。因此，肌腱病描述了一种复杂的、多方面的肌腱病理，临床特征是与活动相关的肌腱疼痛、功能下降、活动受限和残疾，最终容易导致肌腱断裂，导致严重的社会经济负担。肌腱组织细胞密度低，肌腱干物质主要由胶原纤维组成，主要成分为I型胶原。胶原纤维对肌腱的抗拉强度很重要，而其他细胞外基质蛋白，如蛋白多糖，可以结合大量的水，提供抵抗压缩力的保护，并有助于材料的整体弹性。我们最近可以证明，作为主要胶原受体之一的整合素α2β1的缺失，对肌腱的整体生物力学稳定性是不利的。在整合素α2β1缺陷的肌腱中，我们可以观察到基质周转增加和蛋白多糖的存在减少。这表明整合素α-2-β-1在肌腱动态平衡和再生中起重要作用。我们可以将细胞外基质的增加与BMP-2的高表达联系在一起，BMP-2能够诱导腱细胞中胶原的表达。然而，退化的部分仍不清楚。这项拟议的翻译研究项目旨在详细阐明和表征整合素α2β1在肌腱内稳态和与年龄相关的降解中的作用和潜在机制，这些作用和机制与人类患者进一步发生的肌腱疾病有关。在体外，我们将分析胶原相关蛋白的失衡是否是整合素α2β1缺陷肌腱质量下降的原因。在体内，我们将在野生型和整合素α2缺陷动物的生理和年龄相关退变条件下，表征小鼠细胞外基质和肌腱质量的稳定性和结构。在翻译方法中，我们将收集组织，分离原代肌腱细胞，并分析肌腱病患者的血液样本，以研究整合素α2及其相关表型是否与肌腱病变增加相关，并进一步阐明胶原结合整合素对肌腱病发展的预测价值。

Aging affects multiple aspects of the anatomy and physiology including the tendons, which connect muscles to bones. It lowers metabolic activity of tendons as well as tissue regenerative potential. Age related structural changes in tendons such as decrease in collagen content reduces mechanical properties of tendons and predisposes them to injury. Tendinopathy thereby describes a complex multifaceted pathology of the tendon, clinically characterized by activity-related tendon pain, decline in function and restricted mobility and disability, finally prone to tendon ruptures altogether leading to a high socio-economic burden. Tendon tissue shows low cellularity and most of the dry mass of the tendon consists of collagen fibrils, with collagen type I as main component. Collagen fibrils are important for tendon tensile strength, whereas other extracellular matrix proteins like proteoglycans can bind large quantities of water, providing protection against compressive forces and contribution to the overall flexibility of the material. We could recently demonstrate that the absence of integrin α2β1, one of the major collagen receptors, is detrimental to overall tendon biomechanical stability. In integrin α2β1 deficient tendons, we could observe an increased matrix turnover as well as reduction of the presence of proteoglycans. This points out to an important role of integrin α2β1 in tendon homeostasis and regeneration. We could link the increased generation of extracellular matrix with a higher expression of BMP-2, which is capable to induce collagen expression in tendon cells. However the degenerative part is still unclear, yet. The proposed translational research project aims to elucidate and characterize in detail the role and underlying mechanisms of integrin α2β1 in tendon homeostasis and age related degradation linking to further tendinopathies that occur in human patients. In vitro, we will analyze if the misbalance in collagen-associated proteins is the cause of inferior tendon quality in integrin α2β1 deficient tendons. In vivo we will characterize stability and structure of murine extracellular matrix and tendon quality under physiological and age-related degenerative conditions in wild type and integrin α2 deficient animals. In a translational approach, we will collect tissue, isolate primary tenocytes and analyze blood samples from patients with tendinopathies to investigate if integrin α2 and its linked phenotype is associated with increased tendon pathology and further elucidate the predictive value of collagen-binding integrins for tendinopathy development.