Thrombopoietic agents enhance bone healing in mice, rats, and pigs
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, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte (MK) 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 (eg, thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.
Authors
- K. Shively
- Aamir Tucker
- Aarti Gautam (ORCID: https://orcid.org/0000-0003-3132-5599)
- Edward F. Srour (ORCID: https://orcid.org/0000-0002-6026-6498)
- Philip Stewart Low (ORCID: https://orcid.org/0000-0001-9042-5528)
- Thomas B. Bemenderfer (ORCID: https://orcid.org/0000-0002-7129-3395)
- Kelli J. Manikowski
- Joydeep Ghosh (ORCID: https://orcid.org/0000-0003-2497-964X)
- W. Christopher Shelley (ORCID: https://orcid.org/0000-0003-1609-4198)
- Patrick L. Mulcrone (ORCID: https://orcid.org/0000-0001-8528-5137)
- Jeffery J. Nielsen (ORCID: https://orcid.org/0000-0002-2329-1299)
- Melissa A. Kacena (ORCID: https://orcid.org/0000-0001-7293-0088)
- Krista L. Jackson (ORCID: https://orcid.org/0000-0002-2394-4579)
- Andrew Engle
- A. R. Wessel
- Mervin C. Yöder (ORCID: https://orcid.org/0000-0003-4354-7631)
- Marta Alvarez
- Paul Childress
- Alexander Brinker (ORCID: https://orcid.org/0000-0003-1315-2137)
- Jonathan S. Harris (ORCID: https://orcid.org/0000-0002-5609-4283)
- Jeffrey D. Rytlewski (ORCID: https://orcid.org/0000-0003-0010-7548)
- Nabarun Chakraborty (ORCID: https://orcid.org/0000-0002-7883-2013)
- Roman M. Natoli (ORCID: https://orcid.org/0000-0002-4182-3244)
- K.S. Griffin
- Jonathan W. Lowery (ORCID: https://orcid.org/0000-0002-9942-2945)
- Ushashi C. Dadwal (ORCID: https://orcid.org/0000-0002-8610-4825)
- Ying‐Hua Cheng (ORCID: https://orcid.org/0000-0001-7871-8141)
- Todd O. McKinley (ORCID: https://orcid.org/0000-0001-6354-7685)
- Jonathan H. Wilhite
- Patrick D. Millikan
- David C. Scofield
- Rasha Hammamieh (ORCID: https://orcid.org/0000-0001-8643-6232)
- Tien‐Min Gabriel Chu (ORCID: https://orcid.org/0000-0002-7190-837X)
- Stewart A. Low (ORCID: https://orcid.org/0000-0002-7387-3545)
- Jeffrey O. Anglen (ORCID: https://orcid.org/0000-0001-9910-6611)
- Stacy Ann Miller
- Monique Bethel
Institutions
- Purdue University West Lafayette (US)
- Richard L. Roudebush VA Medical Center (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Marian University - Indiana (US)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- Journal of Bone and Mineral Research
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1093/jbmr/zjae191
- Citations
- 2
- Primary Topic
- Blood transfusion and management
- Type
- article
- Field-Weighted Citation Impact
- 0.45
Funders
- U.S. Department of Defense
- Indiana Clinical and Translational Sciences Institute
- Indiana University Health
- Orthopaedic Trauma Association
- National Institutes of Health
- Medical Research and Materiel Command