Thrombopoietic Agents: Novel Osteoinductive Agents for Bone Healing. Thrombopoietic Agents: Novel Osteoinductive Agents for Bone Healing

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically BMPs , has gained wide appreciable attention. However, multiple side effects, including increased incidence of cancer, has renewed interest in investigating other alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte growth factor, thrombopoietin (TPO) and/or second generation TPO agents in mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical sized defect or CSD and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances angiogenesis, an important aspect of successful bone repair. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (e.g. thrombocytopenia). Overall design: n=12, 3 treatments (Saline, BMP-2 and TPO) and 4 replicates of each treatment

实现骨愈合仍是临床面临的重大难题。骨诱导因子（osteoinductive agents）的应用，尤其是骨形态发生蛋白（Bone Morphogenetic Proteins, BMPs），已获得广泛且可观的关注。然而，其存在包括癌症发病率升高在内的多种副作用，使得学界重新关注探索更安全且有效的骨再生替代方案。本研究证实了主要巨核细胞生长因子（megakaryocyte growth factor）——血小板生成素（thrombopoietin, TPO）及其第二代TPO制剂，在小鼠、大鼠与猪体内展现出优异的骨愈合能力。该骨愈合活性在两种骨折模型（临界骨缺损（critical sized defect, CSD）模型与闭合性骨折模型）中，以及局部给药或全身给药方式下均得到验证。本研究通过转录组学分析（transcriptomic analyses）、细胞实验与蛋白质芯片（protein arrays）实验证实，TPO可促进血管生成（angiogenesis）——这是成功骨修复的关键环节之一。此外，促血小板生成制剂（thrombopoietic agents）已在临床用于其他适应症（如血小板减少症（thrombocytopenia）），因此其治疗潜力可观。实验整体设计：每组样本量n=12，设置3种处理组（生理盐水组、骨形态发生蛋白2组与TPO组），每种处理设置4个重复。