Drug repurposing of the anti-fibrinolytic drug tranexamic acid in orthopedic trauma surgery – preclinical and mechanistic studies in mouse models with osteoporosis, fractures, or their combination.

骨质疏松症和骨折愈合受损具有很高的患病率，其特征是骨细胞和巨噬细胞活性的改变。在这方面，我们之前的研究表明，纤溶酶原抑制剂氨甲环酸（TXA），一种广泛应用于骨科手术的抗纤溶药物，在体外刺激成骨细胞增殖，抑制破骨细胞形成，调节巨噬细胞免疫反应。由于一些证据表明TXA对肌肉骨骼疾病的有益作用独立于其在凝血系统中的作用，因此该项目旨在评估其在骨质疏松症和骨折愈合中的治疗潜力。患有ovx诱导的骨丢失、用外固定架稳定的截骨术或两者联合治疗的WT小鼠将接受TXA治疗。此外，全球缺乏纤溶酶原的小鼠将采用相同的程序来确定TXA的纤溶酶原非依赖性效应。骨转换和骨折愈合将使用最先进的放射学、组织学和生化结果测量进行评估。体内实验将辅以细胞培养分析，以测试替代TXA受体的潜在参与。同时，在接受胫骨高位截骨术的患者的临床队列中，将评估全身或局部TXA治疗对骨愈合的潜在影响。胫骨高位截骨术是一种高度标准化的手术，用于相对年轻和健康的早期和单侧膝关节骨关节炎患者。通过结合提出的工作包，该项目有望提供必要的转化证据，以进一步评估是否有必要进行研究TXA新治疗适应症的前瞻性试验。

Osteoporosis and impaired fracture healing have a high prevalence and are characterized by an alteration in the activity of bone cells and macrophages. In this regard, we previously showed that the plasminogen inhibitor tranexamic acid (TXA), an anti-fibrinolytic drug widely used in orthopedic surgery, stimulates osteoblast proliferation, inhibits osteoclast formation, and modulates macrophage immune responses in vitro. As several lines of evidence suggest a beneficial effect of TXA in musculoskeletal disease independent from its role in the coagulation system, the project is designed to evaluate a therapeutic potential in osteoporosis and fracture healing. WT mice with OVX-induced bone loss, with osteotomies stabilized with an external fixator, or with their combination will be treated with TXA. Additionally, mice lacking plasminogen globally will be subjected to the same procedures to identify plasminogen-independent effects of TXA. Bone turnover and fracture healing will be assessed using state-of-the-art radiological, histological, and biochemical outcome measures. In vivo experiments will be complemented by cell culture assays to test a potential involvement of alternative TXA receptors. In parallel, potential effects of systemic or local TXA treatment on bone healing will be assessed in a clinical cohort with patients receiving a high tibial osteotomy, a highly standardized surgical procedure for early and unilateral osteoarthritis of the knee in comparatively young and healthy patients. Through the combination of the proposed work packages, the project is expected to provide the necessary translational evidence to further estimate whether prospective trials studying novel treatment indications of TXA are warranted.