Research Summary Research topic:
Studying the role the blood clotting (coagulation) system plays in bone development, degeneration and repair. Research results:
Manipulation of the coagulation system in a manner to reduce fibrin accumulation in bone could restore development and trigger a renewed capacity to heal bone following injury or prevent the onset of degenerative skeletal conditions. Patient care application of results:
Noninvasive treatments, or prevention, for patients who have skeletal growth development disorders, such as Perthes Disease, degenerative diseases, such as osteoporosis, and those predisposed to fracture non-union such as diabetics and smokers. Simplified patient care application:
Application of drug therapies currently used to treat problems of clotting, such as heart and vascular disease, to improve development and healing of bones and fight degenerative skeletal diseases.
Connecting Science to Care
OREF grant recipient is translating coagulation research into bone health
Jonathan Schoenecker, MD, PhD, was drawn to treating children with hip disorders, such as Perthes disease, because of the dramatic improvement surgery can make in their lives—allowing them to run, play, and grow normally. But the two-time Orthopaedic Research and Education Foundation (OREF) grant recipient also envisions a day when these children will be able to attain normal development and movement without surgical intervention.
Dr. Schoenecker, assistant professor of orthopaedics, pharmacology, pathology, and pediatrics at Vanderbilt University Medical Center, Nashville, Tenn., is enthusiastically pursuing research that may implicate fibrin as an etiologic factor for disturbances in growth and fracture healing as well as a cause of osteoporosis. If he is successful, it would be the first strong evidence that an imbalance of coagulation can result in pathologic skeletal disorders. And that could mean that pharmacologic manipulation of the coagulation system could lead to treatments for numerous skeletal disorders, improve fracture healing, prevent osteoporosis, and speed implant integration.
Dr. Schoenecker shows his patients’ parents what the future may hold by sharing graphic exhibits from his lab work that depict the relationship between vascular problems and stunted growth. He explains that finding a way to adjust key coagulation proteins may help remedy a disorder like Perthes disease and allow bones to grow normally. Dr. Schoenecker believes that talking with his patients and their families is the ultimate measure of a translational question: Can a researcher explain in a few sentences how his or her work in the lab fits within the broader work of treating patients?
“Of course, the first thing the parents ask is ‘Can’t you do something about it now?’” Dr. Schoenecker said. “I eagerly anticipate the day when I can say, ‘Yes, we can.’”
Dr. Schoenecker’s fascination with coagulation began when he earned his PhD while in medical school. As a future pediatric orthopaedist, he was interested in the coagulation system of children, which differs greatly from that of adults, and why its maturation coincides with skeletal development.
Following his graduate work during residency, Dr. Schoenecker continued to develop his current hypothesis as he learned bone biology. He found that skeletal growth requires precise temporal and spatial development of vascular networks. Any disruption in this process results in stunted growth, limb length discrepancies, or joint malalignment that may predispose children to early arthritis in adulthood.
In 2006, an OREF Resident Grant enabled Dr. Schoenecker to put his hypothesis to the test. His study on the function of the coagulation receptors on osteoblasts found that the coagulation protease plasminogen, which is responsible for removing fibrin clots, also played an important role in osteoblast mediated mineralization.
To extend his findings in vivo, Dr. Schoenecker studied bone biology in mice that had an imposed genetic deficiency in plasminogen. He determined that these mice had diminished vascularity, reduced height, failure of ossification, osteoporosis, and poor fracture healing compared to the control group. These results suggested that plasminogen was essential for bone biology, but it didn’t explain why.
The next step was to determine whether the skeletal problems in plasminogen-deficient mice were caused by accumulation of fibrin clots. Dr. Schoenecker hypothesized that reducing fibrin accumulation, either by genetic manipulation or pharmaceutical treatment, would allow longitudinal growth and skeletal development to resume. In 2012, OREF awarded Dr. Schoenecker a Career Development Grant to support this research.
Moving forward, Dr. Schoenecker and his team will decrease the levels of fibrin in plasminogen-deficient mice and in a control group. Some mice will be genetically bred to be deficient in both plasminogen and fibrin. In other mice, fibrin will be pharmaceutically manipulated through either a plasminogen-independent alternative fibrinolytic administered via osmotic pump or a “knock down” of fibrin through a drug injected subcutaneously on a weekly basis.
The team will monitor temporal development of longitudinal growth, as well as vascular development, skeletal architecture, and cellular composition. Dr. Schoenecker hopes that once the amount of fibrin is reduced, the plasminogen-deficient mice will experience restoration of skeletal development, vascularity, and ossification. These results would suggest that while fibrin prevents life-threatening bleeding, too much fibrin can impede vascularity and bone biology.
That would support his hypothesis that pharmacologic treatments could be developed to rectify an imbalance of coagulation and to jump start healing in patients—good news for the children he treats, as well as for many others.
To support clinical trials, Dr. Schoenecker intends to apply for a National Institutes of Health (NIH) RO1 grant.
Excellent ideas, essential support
Dr. Schoenecker notes that OREF’s support has been essential to his research. It gave him his first opportunity to test this hypothesis as a resident, and now it provides his research team the time needed—3 years—to gather sufficient data. Dr. Schoenecker said too many surgeons have excellent ideas to improve patient care, but not enough time to pursue the funding needed to research those ideas.
“What often happens is surgeon scientists will have excellent preliminary data, but are a year or two shy of what they need to obtain NIH support. Without additional funding at this point, many are forced to conclude that it’s not going to work,” Dr. Schoenecker said. “This OREF award is critical in bringing our research to the next level.”
In addition, he believes that foundations such as the OREF are essential to the future of bone research in the face of tough economic times, with fewer research dollars funding bone biology.
“Many institutional funders are not interested in backing orthopaedic research because in their minds it’s just a bone,” Dr. Schoenecker said. “People fail to realize the impact a healthy skeleton has on overall health and longevity. I hope that our research, as well as other OREF-supported research, continues to advance our understanding of bone biology so that we can better care for our patients.”