Thrombopoietic agents enhance bone healing in mice, rats, and pigs

Abstract

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, has renewed interest in investigating 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 second generation TPO agents using multiple animal models including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (e.g., thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.

Keywords: Bone healing; Bone regeneration; Bone repair; Fracture; Thrombopoietin.