Browsing by Author "Wessel, Alexander R."

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    Thrombopoietic agents enhance bone healing in mice, rats, and pigs
    (Oxford University Press, 2024) Childress, Paul J.; Nielsen, Jeffery J.; Bemenderfer, Thomas B.; Dadwal, Ushashi C.; Chakraborty, Nabarun; Harris, Jonathan S.; Bethel, Monique; Alvarez, Marta B.; Tucker, Aamir; Wessel, Alexander R.; Millikan, Patrick D.; Wilhite, Jonathan H.; Engle, Andrew; Brinker, Alexander; Rytlewski, Jeffrey D.; Scofield, David C.; Griffin, Kaitlyn S.; Shelley, W. Christopher; Manikowski, Kelli J.; Jackson, Krista L.; Miller, Stacy-Ann; Cheng, Ying-Hua; Ghosh, Joydeep; Mulcrone, Patrick L.; Srour, Edward F.; Yoder, Mervin C.; Natoli, Roman M.; Shively, Karl D.; Gautam, Aarti; Hammamieh, Rasha; Low, Stewart A.; Low, Philip S.; McKinley, Todd O.; Anglen, Jeffrey O.; Lowery, Jonathan W.; Chu, Tien-Min G.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    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.
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    Thrombopoietin: A Novel Bone Healing Agent
    (Office of the Vice Chancellor for Research, 2013-04-05) Engle, Andrew; Bemenderfer, Thomas; Bethel, Monique; Millikan, Patrick D.; Wessel, Alexander R.; Cheng, Ying-Hua; Wilhite, Jonathan H.; Chu, Tien-Min Gabriel; Kacena, Melissa A.
    Critical-size defects in bones do not heal spontaneously and usually require the use of grafts. Unfortunately, grafts have several limitations. To improve bone formation, many clinicians now use bone morphogenetic proteins (BMP), particularly in spinal fusion, fracture healing, and in critical-size defect regeneration. However, multiple side effects of BMP treatment have been uncovered including increased incidence of cancer. Thus, there is great interest in alternatives that allow for safe and effective bone regeneration. Here we show the ability of thrombopoietin (TPO), the main megakaryocyte growth factor, to heal critical-size femoral defects rodents. 5mm or 4mm segmental defects were created in the femur of Long Evans rats or C57BL/6 mice, respectively. The defects were filled with a novel bioabsorbable scaffold which was loaded with recombinant human TPO, BMP-2, or saline, and held stable by a retrograde 1.6 mm intramedullary Kirschner wire (rats) or 23G needle (mice). Xrays were taken every 3 weeks in rats and weekly in mice. Animal were sacrificed at 15 weeks, at which time micro-computed tomography (μCT) and histological analyses were performed. The results observed in mice and rats were similar. The saline control group did not show bridging callus at any time. Both the BMP-2 and TPO groups healed the defect, although bridging callus was evident at earlier times in the BMP-2 groups. However, the TPO groups showed a much more remodeled and physiologic contour on both Xray and μCT. μCT and histological analysis confirms that compared to BMP-2, TPO-treated specimens have a thicker cortex but smaller diameter and smoother contour. TPO appears to restore the original bone contour by stimulating osteoblastogenesis, allowing for periosteal bridging and stabilization to occur, while simultaneously stimulating osteoclast formation. Thus, TPO may serve as a novel bone healing agent.