Osteoimmune Mechanisms of Segmental Bone Fracture Healing and Therapy
Abstract
The number of segmental fractures is significantly higher in military personnel than in the general population due to training and combat-related stress. Despite efforts with surgery to implant fixators, intramedullary nailing, and invasive plate fixing to heal segmental fractures, unfortunately, lingering effects remain. In such cases, the osteopenic condition leads to permanent atrophic nonunion. Hence, the treatment of atrophic fracture nonunion from large segmental defects continues to represent a therapeutic challenge. Large segmental osteopenia is often seen in patients who received uniplanar or hybrid external fixators as the definitive method of fixation for high-energy fractures, and this adds more difficulties to the treatment of fracture nonunion. This necessitates the importance of identifying and developing novel therapies by understanding molecular and cellular interactions during critical phases of fracture healing. In order to develop an effective approach to cure segmental bone fractures, it is essential to understand additional mechanisms that play a crucial role in bone healing through participation of cells other than osteoblasts, osteoclasts, and their respective progenitors. Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis (formation of new bone for effective remodeling of the fractured area) and angiogenesis (formation of new blood vessels after traumatic injury that occurs during bone fracture) are known to work in concert to control many stages of this process, but when one is impaired, it leads to failure of fracture healing. During fracture repair, there is an abundant infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but also exert influence on neovasculature. Several studies and therapeutic strategies using recombinant osteogenic factors and surgical attempts using metal fixators and pins have been successful in a vast majority of bone fractures. However, if the fractures are long, they remain a big challenge for proper healing, which eventually leads to atrophic nonunions. Hence, it becomes apparent that novel treatment approaches need to be developed and tested apart from conventional approaches. Following bone fractures, there is a high influx of host immune cells in the area. Although primarily they were known to fight infection and aid in the removal of dead cells and debris, current understanding clearly points to their role in establishing tissue remodeling, including new blood vessel formation. This aspect of tissue regeneration, influenced by immune cells, occurs through mobilization of endogenous progenitors that form new blood vessels and bone. The new line of data points to the fact that specialized subset of cell(s) and such cell-produced chemicals should play a key role in fracture healing, failure of which leads to non-union defects, often encountered from long segmental fractures. Towards establishing a novel therapy based on the initial clue that infiltrating immune cells provide key signals for fracture healing and encouraging preliminary results, this proposal will characterize the role of a unique immune cell type, known as immature myeloid cells (IMC) in healing of segmental bone fracture using a preclinical, immunocompetent mouse model. Studies will encompass a detailed analysis of IMC function in bone healing through enhancement of cellular and molecular signals on endothelial cell invasion, migration, and proliferation, aiding in proper ossification and healing. Overall, the studies will test the hypothesis that signals provided by IMC play a crucial role in interfacing sequential events of angiogenesis and osteogenesis that are vital for proper bone healing. The proposal will address a unique and important, yet unexplored, area of the role of key immune cells in providing crucial signals necessary to coordinate the events of angiogene
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510314
Entities
People
- Selvarangan Ponnazhagan
Organizations
- United States Army
- University of Alabama at Birmingham