Researchers from the University of Rochester Medical Center have received a $7.8 million grant to speed the conversion of basic bone science into new treatments that prevent arthritis, improve fracture healing and save limbs. In one case, the research aims to confirm preliminary findings that a handful of patients, previously confined to wheelchairs by fractures that would not heal, were able to walk again after receiving a drug treatment that finally healed the bone.
The award is the first of its kind, a Center of Research Translation (CORT) grant in orthopaedics from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. It is part of a larger effort by the National Institutes of Health (NIH) to fast-track basic scientific findings into meaningful clinical treatments (translational research). With this latest grant, the Department of Orthopaedics and Rehabilitation at the Medical Center becomes the best funded of its kind in the nation in terms of NIH research dollars, according to a new ranking for the most recent NIH fiscal year.
The Rochester CORT will explore new ways to heal trauma to bone and cartilage caused by aging and injury. About 3.6 million Americans suffer trauma to bones or soft tissue each year, with the worst damage caused by car crashes, gunshot wounds and falls. The number of orthopaedic injuries has increased in recent years as baby boomers age, and as U.S. soldiers in Iraq continue to suffer severe injuries.
"We are getting close to the point where decades of research finally pay off in new treatments that restore trauma patients' ability to walk and use their limbs," said Randy N. Rosier, M.D., Ph.D., chair of the Department of Orthopaedics and Rehabilitation at the Medical Center. "We believe our new center will play a key role in a nationwide effort to reverse long-term disability," said Rosier, also principal investigator for the grant.
Research Highlights
Led by Rosier, the first CORT research project will seek to develop ways to predict who is likely to suffer from osteoarthritis in the knee after injury to the meniscus, the sponge-like layer that protects joints from the impact of running and jumping, and then to create a targeted drug therapy to stop it. As many as 40 percent of young patients who sustain meniscal tears in the knee joint following injury have damaged the cartilage of the surface of the joint. Over time, this damaged cartilage deteriorates to become a leading cause of osteoarthritis, which causes joint inflammation and pain in 40 million Americans.
The researchers believe that damage to the meniscus mistakenly switches on a normal repair process by which cartilage is transformed into bone, but in the wrong place, damaging the bone. Perhaps as part of a faulty repair attempt, the meniscus, when injured, makes large amounts of inflammatory proteins that suppress levels of transforming growth factor (TGF-beta), a protein that regulates bone formation. Early research shows that without adequate amounts of TGF-beta, cartilage matures into bone inappropriately, worsening the damage to the joint. With the mechanisms clarified, researchers hope to design new drugs that selectively counter the suppression of TGF-beta in the joint to prevent the problem.
The second research effort will be led by Regis O'Keefe, M.D., Ph.D., associate chair of the Department of Orthopaedics and Rehabilitation, as well as director of the University's Center for Musculoskeletal Research. O'Keefe's program aims to understand how aging delays fracture healing, particularly in relation to an enzyme called cyclooxygenase-2 (COX-2). COX-2 is the same enyzme targeted by popular pain relievers called COX-2 inhibitors (e.g. Celebrex). In past studies, researchers have shown that COX-2 is present at higher levels during fracture healing. As a person ages, however, COX-2 levels dip, and the current project is designed to clarify the reasons why. More importantly, researchers seek to use this information to develop strategies to improve fracture healing in elderly patients.
Taking the next step, a team led by J. Edward Puzas, Ph.D., professor of Orthopaedics, and Susan Bukata, M.D., assistant professor of Orthopaedics, will launch a clinical trial to see whether teriparatide, a fragment of parathyroid hormone, can correct for lower levels of the COX-2 enzyme in older patients. Parathyroid hormone (PTH) regulates the processes of bone formation and recycling. Teriparatide is an approved treatment of osteoporosis under the brand name Forteo, but researchers believe it may also raise levels of COX-2 in the area of a fracture.
In the new study, 50 patients over the age of 55 with pelvic fractures will be randomized to receive either teriparatide or saline once a day for three months. This line of research is based on preliminary cases where patients with osteoporosis confined to wheelchairs by pelvic fractures, or to neck braces by spinal fractures, that would not heal, regained the ability to walk or move after being treated with Forteo.
The third research area, led by Edward M. Schwarz, Ph.D., professor of Orthopaedics, will test a new method for replacing large segments of bone that are too shattered to heal, or are simply missing, to prevent amputation. Bone loss is an urgent issue for car crash victims, bone cancer patients and troops injured in the Middle East. Dead bone donated from cadavers is currently used to replace large portions of missing bone in trauma patients.
Unlike live bone, dead bone neither re-grows new blood vessels (re-vascularizes) nor recycles and replaces old bone (remodels). Thus, daily wear and tear causes unrepaired microfractures to accumulate in large dead bone transplants (allografts), and more that 50 percent fail within 10 years. Schwarz's lab has developed a gene therapy with the potential to trick the body into revascularizing and remodeling transplanted bone, making transplants more likely to succeed over time.
The CORT grants were awarded to four of the 28 institutions that applied, with successful applications proposing a large body of related research with potential for dramatic impact on specific diseases. All the winning proposals included research ready to be tested in human trials.
"I believe the team's combined work will lead to new ways of treating patients with musculoskeletal diseases worldwide," O'Keefe said. "An added benefit is that our department has become a national leader in musculoskeletal research at a time when research funding from the NIH is on the decline."