OREF grant recipient searches for new treatments
A number of factors influence the risk of delayed union or nonunion after fracture treatment, including the fracture site, severity of injury, patient age, nutrition, tobacco use, and diabetes. Delays or failures to heal result in more intensive medical care, a decline in quality of life, and increased expenses. To improve outcomes in these difficult cases, investigators have been exploring means to identify and alter biologic barriers to healing.
“Why do some people heal and some don’t? It’s unclear,” stated Debbie Yen-Dao Dang, MD, PhD, an orthopaedic surgery resident at the University of California, San Francisco (UCSF). “Presumably it’s about the biology of each patient. As orthopaedic surgeons, we would benefit from understanding this biology and developing medications to promote fracture healing.”
Dr. Dang has been investigating the possible role of a transmembrane protein called cadherin 11. Her work was funded in part by a 2015 Orthopaedic Research and Education Foundation (OREF) Resident Clinician Scientist Training Grant. The one-year OREF grant awards $20,000 to enable a resident to prepare for a career with research as a major component. OREF funding for the grant was made possible by the Ira A. Rochelle Family Foundation.
A tale of two proteins
Previous research with animal models demonstrated the importance of intracellular signaling proteins during fracture healing. However, these intracellular molecules are difficult to access from a pharmacologic standpoint.
Dr. Dang noted, “Although [such intracellular proteins] have been studied extensively in the skeletal system, a class of proteins expressed on the cell surface have not been investigated.”
These proteins, called cadherins, play an important role in cell-to-cell adhesion. In other organ systems, cadherins have been shown to interact with intracellular signaling molecules to affect overall cellular, tissue, and organ activity.
“Given this close relationship in other systems, it is reasonable to think that cadherins play an important, yet unknown, role in skeletal processes, including fracture healing,” Dr. Dang explained.
Dr. Dang is interested specifically in cadherin 11, which is expressed relatively specifically in the skeletal system. As a transmembrane protein in bones and cartilage, it provides a kind of portal to intracellular activity. Both factors make it a good candidate for exploring pharmaceutical interventions. “A transmembrane protein is really attractive as a drug target,” stated Dr. Dang. “If we could find something with an affinity to cadherin 11 on the outside of the cell, we might affect what’s going on inside and promote processes that help with fracture healing.”
Modeling fracture healing in the lab
In her investigation, Dr. Dang characterized fracture healing in mouse models. Each mouse underwent a procedure under anesthesia to create a tibial fracture that could be consistently replicated. Mice were monitored and treated for pain. Sets of mice were sacrificed at multiple time points to enable radiographic and molecular assessments at different stages in the healing process.
One aim of the study was to identify the spatial and temporal expression of cadherin 11 during healing. A second aim was to compare fracture healing in genetically normal mice and mice that had the gene for cadherin 11 disabled.
Dr. Dang explained, “Comparing the two groups can answer important questions. Do these fractures look different when they’re healing? Does the fracture heal better in one group than the other? And what are the differences in the types of proteins expressed in each fracture site throughout the healing process? When we understand the basics of what happens when a bone is broken, we can build on that and develop treatments and diagnostics.”
Jay D. Lenn is a contributing writer for OREF. He can be reached at email@example.com.
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