Date of Completion
Aditya Tadinada, Alan G Lurie, Hicham M Drissi
Field of Study
Master of Dental Science
Enhancing bone repair is the key process which facilitates the improvement of fracture healing outcomes. Despite of many studies regarding osteogenesis induction, Bone morphogenetic proteins-2 (BMP-2) and Platelet-derived growth factor-BB (PDGF-BB) are still the only two the Food and Drug Administration (FDA)-approved treatment1, 2. To develop potential treatment modalities, it is essential to understand the role of transcription factors in fracture healing and how they may be specifically targeted in preclinical models to enhance bone regeneration. While the Runt-related transcription factor 2 (Runx2) is known to play a crucial role in osteoblastogenesis, the role of Runx3, a homologue of Runx2, in osteoblastogenesis remains unclear. Our laboratory has previously reported that targeted deletion of the Runx3, in the periosteum resulted in enhanced fracture healing by increased bone formation and biomechanical properties of the fracture callus in mutant mice3. Other factors participate in fracture healing including inflammatory cytokines. They are known to be involved in fracture healing by initiating the repair process following injury. Recent studies demonstrated that one of the most important inflammatory cytokines controlling fracture healing was Interleukin 17 (IL-17)4. It was previously published that IL-17 was expressed by mesenchyme cells, periosteal cells, and chondrocytes within the fracture calluses of wild type mice5. The goal of this study was to investigate the mechanism of how Runx3 regulated fracture healing and the role of IL-17 in this process for future translation into a preclinical model of fracture healing. The hypothesis was that conditional knockout of Runx3 in the periosteum would enhance osteogenesis through upregulation of IL-17 signaling. To investigate this hypothesis, Runx3 expression was conditionally abrogated in limb mesenchymal progenitors. Paired related homeobox 1 (Prx1)-Cre Runx3 F/F mice, which lacked Runx3 activity were compared to control mice (Runx3 F/+) with 100% Runx3 activity. Mid-diaphyseal fracture surgery was performed on 12 week-old female mice, and the mice were then euthanized at 7, 14, and 21 days post-fracture followed by harvesting femurs for molecular and histology analysis. The absence of Runx3, IL-17A and IL-17RA were confirmed by RT-PCR. The localized expression of IL-17A and the receptor IL-17RA was assessed by immunohistochemistry to identify which cells were responsible for the changes in expression.
Matsumura, Satoko, "IL-17A and the Receptor are Regulated by Runx3 during Fracture Healing" (2017). Master's Theses. 1154.
Marc F. Hansen