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.

抗纤溶药物氨甲环酸在骨科创伤手术中的药物再利用——骨质疏松、骨折或其组合小鼠模型的临床前和机制研究。

• 批准号: 515091613
• 负责人: Professor Dr. Johannes Keller, Ph.D.
• 金额: --
• 依托单位: Sektion Experimentelle Unfallchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515091613?language=en
• 关键词: Drug; repurposing; anti; fibrinolytic; drug

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.

骨质疏松症和骨折愈合受损的发病率很高，其特征是骨细胞和巨噬细胞活性的改变。在这方面，我们之前已经证明了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，并调节巨噬细胞免疫反应。有几条证据表明，TXA在肌肉骨骼疾病中的有益作用独立于其在凝血系统中的作用，该项目旨在评估其在骨质疏松症和骨折愈合方面的治疗潜力。患有OVX诱导性骨质丢失的WT小鼠、使用外固定器稳定的截骨术小鼠或两者结合的小鼠将接受TXA治疗。此外，全球范围内缺乏纤溶酶原的小鼠将接受相同的程序，以确定TXA对纤溶酶原非依赖性的影响。骨周转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方法进行评估。体内实验将由细胞培养试验补充，以测试替代TXA受体的潜在参与。同时，全身或局部TXA治疗对骨愈合的潜在影响将在接受胫骨高位截骨术的患者的临床队列中进行评估。高位胫骨截骨术是一种高度标准化的手术程序，适用于相对年轻和健康的患者的早期和单侧膝骨性关节炎。通过拟议的一揽子工作组合，该项目有望提供必要的翻译证据，以进一步评估研究TXA新治疗适应症的预期试验是否合理。