Dean's Newsletter

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NIH Center of Research Translation
"Translating Molecular Signal Pathways to Orthopaedic Trauma Care"

April 27, 2006

It's a true pleasure to report that, in the midst of the understandable concerns about the impact of a declining NIH budget for research on the scientific enterprise, both in Rochester and nationally, we have recently learned of a shining success story in our Department of Orthopaedics and Center for Musculoskeletal Biology. An application for a Center of Research Translation (CORT) to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), entitled "Translating Molecular Signal Pathways to Orthopaedic Trauma Care" (P.I.: Randy Rosier, MD, PhD), received the highest score among approximately 25 applications received by the study section, and will receive $5.6 in direct-cost funding over the next 5 years to study the biological basis of fracture healing and the efficacy of an exciting new potential treatment.

In this newsletter, we will provide a brief summary of what NIAMS is trying to accomplish with this CORT, an overview of the Rochester proposal and why it was so exquisitely responsive to the RFA, a summary of each of the main projects, and a hint to the future of musculoskeletal investigation vis-à-vis two of our MD-PhD students who have received awards in connection with their research.

In its RFA inviting CORT applications, NIAMS made it clear that to be successful, the proposed CORT would have to be highly translational in nature, directed at elucidating the relevance of basic research to human disease in an area within the NIAMS mission. It was stated that two major features of the CORT program must be: 1) the overarching aim of disease-specific research translation, and 2) the inclusion of resources and an administrative structure to facilitate research translation.

Translational research was defined in the RFA as "applied and clinical scientific research that is directed towards testing the validity and limits of applicability of knowledge derived from basic science and engineering to the understanding of human diseases and health." It was also emphasized that the CORT should encompass a multidisciplinary approach to a disease-targeted theme, with individual projects relating to the overall theme.

Randy Rosier, MD, PhD

In the Rochester CORT, the overall research theme relates to orthopaedic trauma. Trauma to bones, joints and soft tissues involves over 3.6 million patients each year in the U.S. alone. Moreover, the number of such injuries has been increasing in recent years due to the aging of the population, and increased physical activity in older individuals. Accidents are the fourth most common cause of death, and the cost of orthopaedic trauma—taking into account medical treatment, lost worker productivity, and rehabilitation costs—is over $20 billion annually. Due to recent military conflicts, problematic severe extremity trauma with bone loss has also increased dramatically.

The individual projects that related to the theme of orthopaedic trauma are focused on three major areas: (1) the impact of meniscal (cartilage) injuries on post-traumatic cartilage degeneration and the development of osteoarthritis; (2) the age-related decline in fracture healing; and (3) a potential solution to the heretofore unsolved problem of segmental bone loss due to trauma.

Several considerations tie these projects together. First, these are very common and problematic injuries that contribute to chronic disability, increased health care costs, and diminished quality of life. Second, there is a common molecular signaling pathway that traverses all of these disorders. And third, novel therapeutic interventions targeted at these signal pathways, which are now becoming clinically available, have the potential to improve significantly the resolution of these common injuries.

Further tying the Center together is the fact that, in contrast to most Centers in which there are several basic science projects and one clinical project that may only be tangentially related, a programmatic environment was created in the Rochester CORT that fosters translation from molecular signaling to clinical trials in each research area. Additional programmatic glue is a Molecular and Anatomic Imaging Core. This Core will not only be used extensively by each project to link molecular and tissue findings in bone and joint trauma with state-of-the-art imaging modalities, but will develop new molecular and anatomic imaging techniques and enhancements to facilitate both the animal and human studies. Also important is the multidisciplinary nature of the CORT research group, involving the Departments of Orthopaedics (Oncology, Sports Medicine, Osteoporosis Center, and Trauma), Pathology, Medicine (Rheumatology and Endocrinology), Biomedical Engineering, Imaging Sciences, and Psychiatry. A key goal, consistent with the NIH Roadmap, is to bring together a multidisciplinary team of clinician-scientists, clinicians and scientists with complementary expertise to foster synergy in advancing the scientific objectives, and translation of the research at all levels to the patient-care arena.

Despite the compelling nature of this application—its clear translational focus on very common clinical problems that are well within the mission of NIAMS, its identification and utilization of a common molecular pathway across projects, its use of both basic and clinical science in all areas of study, its multidisciplinary approach, and its testing of an exciting new potential treatment—Dr. Rosier was still skeptical about our chances in the review process. After the grant was submitted, I remember him commenting that "the study section members and the other applications almost all come from a medicine and/or rheumatology background. I don't know how an application coming from a Department of Orthopaedics will fare." Not only did it fare well, in the sense that it was funded, but in a stunning and extremely satisfying fashion, the Rochester CORT received the best score of all applications.

Dr. Regis O'Keefe

Let's now consider each of the studies included in the CORT. Dr. Rosier is P.I. on the project concerning osteoarthritis following meniscal injury to the knee. This project will use murine models and genetic approaches to confirm the critical role of a novel intracellular pathway controlling cartilage degeneration following mechanical injury. These models will be used to test a possible therapeutic approach to prevent osteoarthritis in mice following meniscal injury. In addition, cartilage markers in patients undergoing arthroscopy for acute meniscal injuries will be analyzed in a clinical trial that will follow these patients with sensitive quantitative MRI scans. "The goal of the trial," Randy states, "is to determine if we can predict who will develop osteoarthritis after meniscal injury, which occurs in nearly 40% of patients. The overall goal is ultimately to be able to predict and prevent osteoarthritis in patients after meniscal injuries to the knee."

Dr. Xinping Zhang

Dr. Regis O'Keefe, Director of the Center for Musculoskeletal Research, is P.I. on the second project, which is aimed towards improving our understanding of two common impairments to fracture healing, aging and nonsteroidal anti-inflammatory drugs (NSAIDs). While most fractured bones normally heal efficiently, this is not the case in elderly patients or patients who receive high levels of NSAIDs for pain management. Dr. Xinping Zhang, Assistant Professor in the Center, previously discovered that COX-2, the central target of NSAIDs, is critical for fracture healing using knockout mice. More recently, Dr. O'Keefe's lab demonstrated that COX-2 is highly expressed during fracture healing in young healthy mice, but is expressed at a much lower level in aged mice. This program is designed to elucidate the cellular and molecular mechanisms responsible for deficient COX-2 expression in aged fracture healing. It will also investigate the ability of the drug Forteo (parathyroid hormone) to overcome these inhibitions. Dr. O'Keefe's project dovetails with Dr. Edward Puzas' clinical trial of Forteo in elderly patients with hip fractures (see below), which provides its translational component.

Dr. Edward Schwarz

Dr. Edward Schwarz is P.I. of the third project, which will further develop the "revitalizing allograft" that his lab published in Nature Medicine last year. In serious fractures when large segments of bone are too shattered to participate in the healing process, or are simply missing, the bone void must be replaced to prevent amputation of the limb. Massive allografts (dead bones from human cadavers) are commonly used for this purpose. While their biocompatibility with host bone allows them to heal at the junctions, the dead bone never revascularizes or remodels. This results in the accumulation of unrepaired microfractures over time until there is a catastrophic failure, which occurs in more that 50% of massive allografts within ten years. Dr. Schwarz's lab has developed a novel gene therapy approach in mice that tricks the host into revascularizing and remodeling the dead bone into live bone. With the help of Dr. Hani Awad, Assistant Professor of Biomedical Engineering, the investigators will demonstrate the superior strength and vascularity of the revitalizing allografts in mice. Towards the clinical translation of this technology, Drs. John Looney (Rheumatology) and Ruola Ning (Radiology) will complete a clinical pilot with a novel cone beam CT scanner that will quantify the changes in vascularity inside the bones of patients who receive structural autografts (live bones) or allografts. According to Eddie, "We are hopeful that this clinical pilot will provide us with the critical outcome measure we need to prove our revitalizing allografts in human trials."

Ed Puzas, Ph.D

Finally, a basic scientist, Ed Puzas, Ph.D. (PI) and an orthopaedic surgeon, Susan Bukata, M.D. (co-PI) have joined forces with a human movement analysis expert from Ithaca College (Jeff Houck, Ph.D. Co-I) and a research psychiatrist from the Dept. of Psychiatry (Barbara Gracious, M.D., Co-I) to launch a randomized clinical trial on the effect of teriparatide on the healing of fragility fractures in the elderly. Teriparatide (brand name Forteo) is a 34-amino-acid fragment of parathyroid hormone that is used in the treatment of patients with osteoporosis. It has the property of expanding the progenitor cell populations for osteoblasts and chondrocytes and thus may also be effective in the treatment of a fractured bone. The research design for a trial such as this was difficult to develop because of the multifacited nature of the healing process. Quantification of the healing is also challenging. Not only must there be a measure of callus formation but the mobility of the subject and their level of pain must be considered. Dr. Puzas and his group devised a series of quantifiable outcomes including functional tests, three dimensional radiographic analyses and pain measures to monitor the effect of the drug. This project is a direct extension of the work in the Center for Musculoskeletal Research designed to understand the mechanisms of fracture healing in animal models. Not only is it a compelling example of how basic science results can potentially be translated into improved medical treatments, but it is also an example of how scientists and clinicians in different disciplines can come together to find solutions to complex problems that affect our health.

Barbara Gracious, M.D.

Dr. Rosier summarizes the overall CORT program as follows: "A scientific approach extending from the molecular level to clinical trials in the area of bone and joint injury has been conspicuously absent in orthopaedics. The CORT RFA provided us with an excellent opportunity to combine our own studies in skeletal tissues with perspectives from a wide range of collaborators in other Departments and Centers to create the bench-to-bedside translational approach that the NIAMS was seeking. The fact that investigators in the Department of Orthopaedics and Center for Musculoskeletal Research already function in a highly integrated and collaborative fashion markedly facilitated the construction of this matrix of interacting basic and clinical projects."

To end this newsletter, we look to the future of musculoskeletal investigation among the ranks of our students. Coming on the heels of Dr. O'Keefe's recent successful training grant application, the CORT helps complete an extensive infrastructure within the Center for Musculoskeletal Research for training of musculoskeletal researchers in basic, translational, and clinical investigation. .

Ruola Ning, PhD

Last year, one of our MD-PhD students, Amish Naik, received a scholarship from the Howard Hughes Medical Institute on the role of aging in fracture repair, a main area of study in the CORT. Preliminary data that Amish produced in his laboratory provided an understanding of the molecular mechanisms related to diminished fracture repair, and of potential ways to improve repair, that served as the basis for several aims in the CORT. Indeed, the project in the CORT that deals with the biological basis and treatment of the age-related decline in fracture healing has become Amish's PhD thesis.

Moreover, last week we learned that Kofi Mensah, a second year medical student (also from the MD-PhD program), was one of five winners in the Research Poster category at the ACP National Medical Student Abstract Competition held recently in Philadelphia. This is an incredible achievement, given that there were 1600 submissions to the national competition. Under the mentorship of Edward Schwarz, PhD and Christopher Ritchlin, MD, Kofi's research on the "Potential Role for Interferon-alpha Therapy in Erosive Arthritis" had earlier won first place in the Medical Student Research Abstract competitions at both the Upstate and Downstate New York ACP Chapter Scientific Meetings. He found that interferon-alpha reduced the potential for osteoclast development from osteoclast precursor cells, thereby advancing previous experimental and clinical observations related to the effects of interferon-alpha on SLE symptoms, and pointing to the potential for using the interferon-alpha pathway in finding new ways to treat osteoclast-mediated bone disease.

Dr. Rosier states, "We are all extremely excited by the news about our CORT application, which will enhance collaborations between basic scientists, clinician-scientists, and clinicians in the study of bone and joint injuries using multidisciplinary approaches. The support will provide a significant infrastructure for translational research, which has been a very high priority of the Department of Orthopaedics and Rehabilitation and the Center for Musculoskeletal Research. The possibility of developing predictive and potentially preventive strategies for osteoarthritis after knee injuries, accelerating fracture healing in the aging, and rapidly converting allograft bone to living bone for reconstruction of bone loss, has created tremendous enthusiasm among the investigative teams, and will generate significant contributions to Orthopaedics."

Meliora,

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry