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RESEARCH BRIEFSGene Initiates Joint FormationThe cells that develop into the bones and synovial joints in a vertebrate appendicular skeleton begin as an uninterrupted grouping of cartilage precursor cells. Little is known about how this continuum of seemingly similar cells segments to form the joints and bones of appendages. Now researchers at HMS have identified a molecule that plays a central role in the initiation of synovial joint formation.
This section of the digits of a developing chick shows the expression pattern of the joint-inducer Wnt14 (shown in white). Wnt14 is expressed in the joint (transverse stripes) and in the surrounding soft tissues, but not in the bone or cartilage adjacent to the joint. Courtesy of Christine Hartmann Studying limb formation in the developing chick, postdoctoral fellow Christine Hartmann and her adviser Clifford Tabin, HMS professor of genetics, found that a previously uncharacterized member of the Wnt family, Wnt14, was expressed early in regions of the embryo that become synovial joints. The presence of Wnt14 in presumptive joint regions early in development led Hartmann and Tabin to investigate the role of Wnt14 in the initiation of joint formation. Their work, which identified "the first gene reported to have the ability to initiate joint formation," says Hartmann, is reported in the Feb. 9 Cell. Using a virus to misexpress Wnt14 in the developing limb, Hartmann and Tabin found that Wnt14 had the ability to induce morphological, histological, and molecular changes characteristic of the initiation of joint formation in places that normally would not form a joint. They determined that Wnt14 acts on cells that are already partially differentiated cartilage precursor cells. In addition to inducing the "dedifferentiation" of these cells, Wnt14 also induces molecular and morphological changes, sending these cells on differentiation paths toward forming a joint. Interestingly, the Wnt14-mediated induction of ectopic jointlike regions inhibited the formation of adjacent joints, suggesting that Wnt14 plays a role in the spacing of joints. Wnt14 is also expressed in mature joints. Changes in the expression of other members of the Wnt family in mature joints have been implicated in rheumatoid arthritis, a disease marked by changes in the synovium. Further characterization of Wnt14 and Wnt14-associated pathways may have implications for the disease. Hartmann and Tabin are now interested in using mice as a model to study whether Wnt14 is essential for the formation of joints and to determine the role of Wnt14 in the development of synovial abnormalities such as those found in rheumatoid arthritis. Radiation Limits Narrowing of Arteries After StentThe placement of a stent following percutaneous angioplasty is often sufficient to prevent an artery from narrowing again. However, recurrent narrowing at the site of the stent, termed in-stent restenosis, occurs in approximately 150,000 patients annually in the U.S. Patients with in-stent restenosis face repeated cardiac procedures including bypass surgery. Now, the results of a multicenter, double-blind, randomized trial directed by the Harvard Clinical Research Institute and the Cardiovascular Data Analysis Center indicate there may be an effective alternative: local intracoronary radiation therapy, or brachytherapy. The first of its kind, the Gamma-One Trial tested the safety and efficacy of the delivery of iridium-192, a source of gamma radiation, in the prevention of in-stent restenosis. Richard Kuntz, HMS associate professor of medicine at Brigham and Women's Hospital, and colleagues found that intracoronary gamma irradiation resulted in significantly less restenosis, and thus a significant decrease in the need for additional cardiac procedures. This study appears in the Jan. 25 New England Journal of Medicine. In what Kuntz calls a "fruitful collaboration," interventional cardiologists and radiation oncologists work together to irradiate the target lesion. After using a catheter to thread a plastic ribbon containing radioactive seeds to the site of restenosis, they irradiate the lesion for approximately 15 minutes. Irradiation may prevent restenosis by blocking the proliferation of arterial cells lining the site of the stent. Although the procedure decreased in-stent restenosis, the benefits of gamma radiation were accompanied by an increase in postprocedural thrombosis and myocardial infarction. These complications were linked to the placement of another stent following irradiation and the discontinuation of antiplatelet therapy. Additional studies suggest that if the placement of a new stent is avoided and antiplatelet therapy is continued, there is no increase in thrombosis or myocardial infarction. As a result, intracoronary radiation therapy "will soon be the treatment of choice for in-stent restenosis," says Kuntz. Growth Factor Seen to Reverse Loss of Muscle from Aging, DiseaseFor years scientists have been studying the potential of a molecule, insulin-like growth factor I (IGF-I), to help repair and even reverse the loss of skeletal muscle function that occurs in aging and disease. Recent work by researchers at Massachusetts General Hospital provides strong evidence that IGF-I may be an effective and potentially safe means of stimulating skeletal muscle growth. Previous work by Nadia Rosenthal, HMS associate professor of medicine, and her colleagues showed that injection of a virus directing the expression of IGF-I into a skeletal muscle resulted in a much larger and stronger muscle. Now research described in the February Nature Genetics by Rosenthal and colleagues illustrates that the effect of IGF-I that they had previously seen "holds up in context of the whole body," Rosenthal says. Transgenic mice that were expressing a particular isoform of IGF-I specifically in their skeletal muscles had significant increases in skeletal muscle mass and strength. In addition, their senescent muscles kept the ability to proliferate in response to damage. Importantly, the change in IGF-I levels in the skeletal muscle did not increase the levels of IGF-I elsewhere in the mice, precluding damage to other tissues that had been seen in different IGF-I transgenic models due to elevated IGF-I. These characteristics make IGF-I "an excellent candidate for gene therapy for diseases such as muscular dystrophy," says Rosenthal. Remarkably, the benefits of IGF-I could be seen in geriatric mice. "We've discovered that IGF-I expression maintains a high number of muscle precursor cells in older animals," says Rosenthal. The potential ability of IGF-I to stave off the effects of aging is exciting because of the possibility of preventing or reversing the muscle frailty that accompanies aging. Rosenthal and her collaborator Antonio Musaro at the University of Rome are currently interested in understanding the signal transduction pathways that allow IGF-I to trigger such dramatic changes in muscle and the effects of IGF-I in animal models of muscular dystrophy. Rosenthal is also collaborating with researchers at the University of Pennsylvania on an IGF-I gene therapy trial. T Cell Response to HIV Proteins May Make Them Vaccine CandidatesStudies of the immune response to HIV-1 infection and the development of a vaccine have long focused on HIV-1's structural proteins. These molecules are expressed relatively late in the viral life cycle, after HIV-1 has decreased the expression of an important set of cellular proteins, the MHC Class I molecules, involved in the body's ability to fight viral infections. Researchers at Massachusetts General Hospital and HMS have now found that two HIV-1 regulatory proteins, Tat and Rev, expressed earlier in the HIV-1 life cycle, are frequently targeted by the immune system of infected individuals. Screening the cells of HIV-1–infected individuals, postdoctoral fellow Marylyn Addo, her adviser Bruce Walker, HMS professor of medicine and director of the Partners AIDS Research Center, and colleagues found that Tat and Rev "contribute to the total cytotoxic T lymphocyte response quite importantly," says Addo. The determination that Tat and Rev are frequently targeted by cytotoxic T lymphocytes, cells critical to fighting HIV infection, indicates that Tat and Rev may be "candidates for a multicomponent HIV-1 vaccine," Addo says. The group's work appears in the Feb. 13 Proceedings of the National Academy of Sciences. Using overlapping peptides that span the entire Tat and Rev proteins, the group also mapped the first described antigenic determinant, or epitope, of Tat and two previously unidentified Rev epitopes. One of these Rev epitopes is presented on a particular MHC class I molecule that is not downregulated by HIV-1. Addo speculates that individuals who develop an immune response to this particular fragment of Rev may fare better against the disease. The researchers are now performing longitudinal studies to determine the duration of the immune response to Tat and Rev. The group is also mapping and characterizing additional Tat and Rev epitopes, an important step toward the development of a vaccine against HIV-1. —Briefs by Heather Ettinger |
