Fall/Winter 2006 - University of Rochester Medical Center

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treatments from the discoveries of basic science. Rochester is one of four institutions to get an initial CORT grant, an award that was based on the potential for dramatic impact on specific diseases and the readiness to test treatments in human trials. Rochester’s CORT project has three major segments: meniscal injuries and the development of osteoarthritis, age-related decline in fracture healing, and segmental bone loss in trauma. The treatment targets are signaling pathways that play critical roles in controlling skeletal cells, in particular, transforming growth factor-beta (TGF-beta) and ligases called Smurf 1 and Smurf 2. Rosier is leading the study of injuries to the meniscus and its consequences. In studies in mice, the research team has found that over-expression of one of the Smurf enzymes in cartilage could cause a form of osteoarthritis. “One of the Smurfs not normally expressed in healthy cartilage is turned on and it blocks the TGF-beta signals that help maintain the health of the cartilage,” Randy Rosier said. “We found that after meniscal injury, the Smurf is turned on in the cartilage adjacent to the injury. We think people who have high expression of it after the injury may Regis O’Keefe, M.D., Ph.D. be the ones who get arthritis.” As part of the project, tissue will be taken from patients who have torn cartilage for studies of gene expression. The patients also will have sophisticated quantitative MRIs that can detect the earliest loss of cartilage or structure. “About 40 percent of patients with meniscal injuries develop arthritis. Within a few years, we’ll know who they are and we can look back at the gene expression,” Rosier said. “We hope to develop a model that allows us to predict who will get arthritis. Then we can help with a therapeutic strategy.” The team also envisions the use of growth factor or a gene therapy that could prevent the development of arthritis. Healing and revitalizing bone Regis O’Keefe, M.D., Ph.D. (R ’92, MS ’00, PhD ’00), professor of Orthopaedics and director of the Center for Musculoskeletal Research, is the principal investigator for the CORT project’s second segment, an investigation of fracture healing. Broken bones in the elderly do not heal as well or as quickly as the broken bones of children. There are several causes for the lessening of the ability to heal. But O’Keefe and his lab team have found a series of genes expressed at 10 ROCHESTER MEDICINE
appropriate levels in young mice that are not expressed at those levels in old mice. One of the genes that is down-regulated, O’Keefe’s team discovered, involves the same Smurf that is a culprit in the development of arthritis. The lab also has shown that COX-2, one of the cyclooxygenase enzymes, may play an important role in maintaining appropriate Smurf levels and appears to be critical for fracture healing. “Smurf helps cause the transformation of cartilage that forms in fracture sites into bone,” Rosier said. “In the joint, that’s a terrible thing, but in fractures, it is part of a normal and necessary process.” The O’Keefe lab also identified an intercellular signaling pathway that controls the Smurf. The project will investigate the cellular mechanisms in maintaining the appropriate levels of Smurf expression and the role of COX-2. A parallel project directed by Puzas and Susan Bukata, M.D., an orthopaedic surgeon, involves a clinical trial of teraparatide, a parathyroid hormone with the brand name Forteo. The hormone stimulates osteoblasts to form bone. When used in treating severe cases of osteoporosis, the hormone can increase bone mass by 15 percent in a year. “One of our notions is that the hormone could substitute for the loss of COX-2 that occurs with aging and restore the signaling that would enable the appropriate levels of the gene to be expressed, so cartilage turns into bone on schedule,” Rosier said. Rosier’s team also is the first to make a dramatic discovery about the hormone’s capabilities when given to patients with pelvic-insufficiency fractures. These stress fractures often fail to heal because they occur in elderly people with other health problems. After discussions with patients with the stress fractures, several received the parathyroid hormone. “Some had been in pain and in a wheelchair for a year,” Rosier said. “ Within a few months of taking the hormone, they walked into the clinic. X-rays showed the fractures had healed. We have now treated about 20 people, with almost all having healed. We have, in fact, had some patients with spine fractures in the neck who have completely healed.” Puzas and his group will quantify and map the healing of fractures in patients in a clinical trial of the hormone. The third major part of the CORT project addresses the revitalization of allografts, the dead bone from human cadavers used to replace bone lost in severe trauma or cancer. Edward Schwarz, Ph.D., associate professor of orthopaedics, is the principal investigator. “The transplanted bone works well mechanically. It will fuse and provide structural support, but it never becomes a fully living bone,” Rosier said. “Fatigue fractures occur, and there’s no ability to repair. Living bone constantly repairs itself. There is a high failure rate in the long term for these allografts. It would be great if we could find a way to convert the graft to a living bone.” Schwarz has conducted in-depth studies of allografts in mice, tracking the cells that produce healing and identifying the growth factors involved. He also has developed a novel gene therapy that, when used in mice, causes a revascularization of the bone and turns the dead bone into living bone. Schwarz will continue his gene therapy in mice to demonstrate the extent and strength of the revitalization. Cone beam computed tomography technology, developed by Ruola Ning, Ph.D., professor of radiology at the Medical Center, will be used to quantify vascularity in human patients who receive allografts. The CORT pilot study will validate use of the technology to quantify bone formation. It also could lead to a clinical trial of a gene therapy that would stimulate revitalization. FALL / WINTER 2006 11
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Fall/Winter 2006 - University of Rochester Medical Center

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