The body depends on complex biologic checks and balances, and activating one molecular pathway toward a therapeutic goal may trigger feedback loops that dampen the effect. Jaimo Ahn, MD, PhD, an orthopaedic trauma surgeon as well as a cell and molecular biologist, wondered whether a feedback loop might be one factor limiting the effectiveness of bone morphogenetic proteins (BMPs) in accelerating bone healing.
“The clinical optimization of fracture healing remains a substantial challenge to society and to surgeons treating individual patients,” said Dr. Ahn. “The discovery of BMPs led to their use to promote posttraumatic healing, but their clinical impact has been less dramatic than we hoped.
“One explanation for this disappointment may be that therapeutically administering BMPs shifts the body’s mechanisms for keeping BMP in check into high gear,” continued Dr. Ahn. “If we could fine tune that process, we might enhance the performance of therapeutic BMP or increase the healing power of the body’s own BMP.”
Dr. Ahn aims to gain insight into BMP and its regulators with a 2010 Young Investigator Grant from the Orthopaedic Research and Education Foundation (OREF). He hopes to learn whether two BMP antagonists, called noggin and sclerostin, may have potential as therapeutic targets to modulate BMP function. He theorizes that inhibiting noggin and sclerostin may increase BMP activity, enhancing its ability to speed healing.
Modulating BMP/antagonist interactions could have orthopaedic implications beyond posttraumatic healing. Monoclonal antibodies against sclerostin, also a powerful Wnt pathway inhibitor, are already under clinical investigation as a new approach to increase bone mass in osteoporosis. And the therapeutic potential could extend well beyond orthopaedics.
Although BMPs were first discovered as a result of their ability to stimulate bone growth, they’re now recognized as part of a larger class of growth factors that determine a wide range of cellular functions throughout the body. BMPs are involved in growth and development in the cardiovascular system, the gastrointestinal lining, and lung and liver tissue. Evidence that BMPs may play multiple roles in human diseases—including primary pulmonary hypertension and colon and esophageal cancers—also exists.
Turning observations into questions
“I’m trying to find a molecular feedback loop in the lab, and as a clinician scientist, I’m trying to establish a professional feedback loop between the lab and the clinic,” Dr. Ahn said. “With a certain depth of basic science knowledge, orthopaedic surgeons can make observations in patient care that can be translated into scientific questions. These questions can be taken back to the laboratory, and the answers found in the lab can be applied to refine care and improve outcomes.”
Dr. Ahn’s OREF-funded project aims to fill gaps in understanding how BMP and its molecular regulators interact in a mouse model of bone healing.
“Animal studies have shown that naturally occurring BMPs are present in healing fractures and that therapeutic BMPs can help stimulate healing,” Dr. Ahn said. “Studies have also shown that BMP antagonists are present as fractures heal, but we don’t know the dynamics of how BMP and its antagonists interact. How does biologic timing govern when BMP and its antagonists appear in a fracture? Does applying therapeutic BMP increase the level of antagonists? If antagonist production increases, does that slow healing? Can we identify small molecules that might enable us to manipulate this complicated molecular system to our therapeutic advantage?”
Dr. Ahn and his team first will administer therapeutic BMP to a group of mice without leg fractures to assess its effect on uninjured bone. Each mouse will be randomized to receive an injection of BMP in either the right or the left leg. The team will then analyze levels of BMP, noggin, and sclerostin in both the treated and untreated legs at five intervals ranging from 12 hours to 21 days.
Dr. Ahn’s group will then inject BMP into a group of mice with both tibias fractured. The mice will be randomized to receive an injection on one side or the other. Similar assessments of molecular benchmarks and levels of healing will be conducted over the same intervals.
Dr. Ahn hypothesizes that therapeutic application of BMP will increase noggin and sclerostin levels. If the team can document this increase—especially if the increase occurs over a predictable time frame—it may be possible to optimize the effects of BMP during the healing cycle by modulating noggin and sclerostin activity. The final goal of the project is to identify small-molecule inhibitors of noggin and sclerostin that could potentially be used in developing drugs in the future.
First response and first causes
As both a trauma surgeon and a cell biologist, Dr. Ahn has a compelling interest in both rapid response to orthopaedic injury and molecular approaches that may drive recovery. He met his first clinician scientist mentor while an undergraduate at Stanford University. That mentor inspired his interest in a career spanning both cutting-edge science and patient-centered care through an MD-PhD program at the University of Pennsylvania (UPenn).
Dr. Ahn was further inspired by Frederick S. Kaplan, MD, and Regis J. O’Keefe, MD, PhD, to integrate science and clinical care in practice. Today he serves as an assistant professor of orthopaedic surgery at UPenn, specializing in trauma, and as a scientist with his clinical partners and his laboratory collaborator, Kurt Hankenson, DVM, PhD, in investigating molecular processes in skeletal injury.
“The basic science side of that clinician scientist equation is harder to keep in equilibrium, especially for a young investigator launching a career. That’s where OREF funding has offered me an invaluable opportunity,” said Dr Ahn. “We’ll always need orthopaedic trauma surgeons, and I’m lucky to serve in a major trauma center providing state-of-the-art care, but clinician scientists need protected time away from clinical responsibilities to launch their research careers. That’s especially challenging when research interests focus on molecular orthopaedics and basic science.
“In the long run, there’s nothing more satisfying than identifying a problem, taking it back to the lab, and finding an answer that may improve patient care,” Dr. Ahn continued. “But I couldn’t embark on this dual career path without OREF support. With therapeutic interest in BMPs and other cytokines increasing, I’m optimistic there will be opportunities for support from the National Institutes of Health and other larger funding bodies. In fact, this work has already attracted additional funding from the Foundation for Orthopaedic Trauma.”
Sally T. Halderman is a contributing writer for OREF and can be reached at firstname.lastname@example.org