Investigating the role of tenomodulin in tendon healing using tenomodulin knockout model

肌腱和韧带是肌肉骨骼系统的力量传递组织，容易发生与年龄相关的退化和随后的创伤性断裂，这是骨科医学的主要负担，由于它们的组织愈合不良，进一步放大了这一负担。肌腱调节蛋白(Tenomodrin，Tnmd)是一种新型的蛋白质，主要在肌腱和韧带中表达，是目前已知的这些组织的基因标志物。我们已经产生了Tnmd基因敲除的小鼠品系，我们的分析表明，Tnmd是肌腱细胞黏附和增殖以及胶原纤维成熟的调节因素，这些过程在肌腱修复过程中也是基本的。此外，我们还发现，Tnmd表达的缺失与心脏肌腱断裂的易感性直接相关。尽管其预期的重要性，我们对TNMD在肌腱病理生理学和修复中的作用的了解是有限的。因此，这项建议的主要目的是获得对TNMD在肌腱愈合中的作用的机械性见解。为了达到这一目的，Tnmd基因缺陷小鼠将被检测：1)手术诱导的跟腱断裂模型；2)宏观和纳米生物力学测试；3)小鼠跑步训练；4)Tnmd RNA和蛋白质形态的体外分析以及小鼠和人肌腱来源细胞的比较。这些互补的实验方法将对肌腱修复和功能有更好的了解，并可能确定TNMD为开发肌腱特异性治疗药物的新靶点。

Tendons and ligaments, the force-transmitting tissues of the musculoskeletal system, are prone to age-related degeneration and subsequent traumatic ruptures, a dominant burden in orthopaedic medicine that is further amplified due to their poor tissue healing. Tenomodulin (Tnmd), a novel type of protein, is predominantly expressed in tendons and ligaments; hence it is currently the best-known gene marker for these tissues. We have generated Tnmd knockout mouse strain and our analysis revealed that Tnmd is a regulatory factor in tendon cell adhesion and proliferation as well as collagen fibril maturation; processes that are also fundamental during tendon repair. Furthermore, we have found that the loss of Tnmd expression is directly associated to the predisposition of heart tendons to rupture. Despite its anticipated importance, our knowledge about the role of Tnmd in tendon pathophysiology and repair is limited. Thus, the primary purpose of this proposal is to gain mechanistic insights into the function of Tnmd in tendon healing. To achieve this aim, Tnmd-deficient mice will be examined in 1) surgically induced rupture model of Achilles tendon, 2) macro and nano biomechanical tests; 3) mouse running exercises and 4) in vitro analyses of Tnmd RNA and protein forms and comparison of mouse and human tendon-derived cells. These complementary experimental approaches will provide a better understanding of tendon repair and function, and may identify Tnmd as a novel target for the development of tendon-specific therapeutic drugs.