10-Year-Old Arthritis Institute Goes Beyond Aches And Pains Of Joints

And Pains Of Joints (The Scientist, Vol:10, #6, p. 13 & 18, March 18, 1996) SEEKING ADVICE: New NIAMS director Stephen Katz is consulting all sectors of the biomedical community to help set institutional priorities. "Chronic, common, costly, and crippling." That's how Stephen I. Katz, director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) since August, describes the diseases that the institute explores. NIAMS is celebrating its 10th anniversary this year. According to NIAMS statistics, one in seven Americans has some form of arthritis; one in three Americans has a serious skin disease; and four of five Americans will have lower back pain at some point in their lives. "We cover over 100 forms of arthritis, all of the musculoskeletal system-from osteoporosis to low back pain to repetitive motion disorders to muscle diseases-and all of the skin diseases. In addition, we cover basic research on the physiology of joints, bones, skin, and muscles," Katz says. What brings these broad areas together, biologically, is that they constitute "the major mass of the body," he explains. PROFESSIONAL SOCIETIES ASSOCIATED WITH NIAMS RESEARCH American College of Rheumatology 60 Executive Park South, Suite 150 Atlanta, Ga. 30329 (404) 633-3777 Fax: (404) 633-1870 E-mail: acr@rheumatology.org World Wide Web site: http://www.rheumatology.org 6,200 members President: Arthur L. Weaver Executive Director: Mark Andrejeski Journals: Arthritis and Rheumatism; Arthritis Care and Research American Society for Bone and Mineral Research 1200 19th St., N.W. Washington, D.C. 20036 (202) 857-1161 Fax: (202) 223-4579 E-mail: sbmr@sba.com 2,700 members President: John P. Bilezikian Executive Director: Julia A. Janko Journals: Journal of Bone and Mineral Research; Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism Biophysical Society 9650 Rockville Pike Bethesda, Md. 20814-3998 (301) 530-7114 Fax: (301) 530-7133 E-mail: society@biophysics.faseb.org World Wide Web site: http://biosci.cbs.unm.edu/biophys/biophys.html 4,000 members President: Stephen H. White Executive Director: Emily M. Gray Journal: Biophysics Journal Society for Investigative Dermatology 11001 Cedar Ave., Suite 500A Cleveland, Ohio 44106 (216) 844-6859 Fax: (216) 844-6810 E-mail: sid@halcyon.com VWorld Wide Web site: http://www.telemedicine.org/sidhome.htm 2,500 members President: Eugene Bower Administrative Director: Angela Walsh Journal: Journal of Investigative Dermatology Another factor tying NIAMS research projects together is that many of these diseases are prevalent in women, such as osteoporosis, lupus, and some forms of arthritis. "We find ourselves easily able to answer questions about what is going on in women's health because we are involved with diseases that are more prominent in women," says bone-disease specialist Joan McGowan, chief of the extramural musculoskeletal diseases branch at NIAMS. She is also a project officer in the National Institutes of Health's Women's Health Initiative. The diseases and parts of the human body that NIAMS now covers were not always so neatly organized under one institutional umbrella. In 1950 the National Institute of Arthritis and Metabolic Diseases was established. In 1972, digestive diseases were added, and the unit changed its name to the National Institute of Arthritis and Metabolism, and Digestive Diseases. In 1980, two more areas were tacked on, and it became the National Institute of Arthritis, Diabetes, and Kidney and Digestive Diseases. Six years later, the Health Research Extension Act of 1985 led to the early 1986 establishment of the National Institute of Arthritis and Musculoskeletal and Skin Diseases to bring increased emphasis on these disorders. NIAMS, with a total appropriated budget of almost $242 million for 1996, has the sixth smallest budget of the 17 NIH institutes. Of that, the bulk-$213 million, or 88 percent-goes to extramural programs. The remaining $29 million funds intramural research and supports the institute's more than 75 intramural scientists and postdoctoral fellows. Diseases studied by NIAMS-funded researchers have a yearly economic impact in the hundreds of billions of dollars: $55 billion for arthritis; $71 billion for musculoskeletal disorders; and $7 billion for skin diseases, according to NIAMS statistics. WOMEN'S HEALTH: We're involved in diseases that are more prominent in women," remarks Joan McGowan, an extramural branch chief. David Pisetsky, a professor of medicine at the Duke University Medical Center and a medical adviser for the Atlanta-based Arthritis Foundation, contends that although NIAMS's resources and staff are small compared with those of some other NIH institutes, "it's always been a first-rate research program." One of Katz's first priorities has been to evaluate how NIAMS resources could be redirected to better meet the public's needs. "The only thing that's really not on the table is the R01 [extramural] funding, because I think that investigator-initiated research is how major scientific advances are made." To conduct this evaluation, he's been talking to all levels of the scientific community affected by NIAMS research, "not just the so-called cardinals. I've been meeting with people who've been in the community for a long time; people who are just starting out; and people who are not yet funded." Observers outside, but familiar with, the institute show confidence in what Katz has done so far. "I think he is taking a very important look at existing programs, recognizing he is now operating in a different era, where resources are not expanding," remarks Pisetsky. "I think he has been extraordinarily open and has started a very constructive dialogue with the entire arthritis community." Evelyn Hess, chairwoman of the medical council of the Rockville, Md.-based Lupus Foundation and the McDonald Professor of Medicine at the University of Cincinnati Medical Center, comments that it's still too soon for Katz's tenure to adequately be assessed. However, she says, "because he's a dermatologist and has an interest in autoimmunity and the immunology of the skin, I'm sure he's going to have an interest in lupus because it has a big skin component." Katz is also chief of the dermatology branch in the National Cancer Institute, the post he held before becoming NIAMS director and one he will retain. During the last decade or two, researchers have changed their thinking about the function of the skin as an organ, realizing that it's not just a covering for more important body parts. "We now know that the skin is not a passive target of immune reactivity, but rather an active immunologic organ on its own," says Alan Moshell, director of the extramural skin diseases branch at NIAMS. Studies in Katz's and others' labs on Langerhans cells and certain types of cytokines-both found in the epidermis-have demonstrated that skin is a critical component of the immune system, both in its protective function and as a first line of defense. Researchers also formerly believed that the skin was "just a passive target of autoimmune attack," notes Moshell. "However, the utilization of molecular genetic technology has allowed the cloning and isolation of particular proteins that are the target of autoimmune attack." Such changes in thinking also have had practical applications. "Going back 15 to 20 years, the skin was also thought of as a layer of cellophane, an inert block to anything going in or out," says Moshell. But now, armed with knowledge that certain substances pass readily through the skin, scientists have targeted topical products, such as estrogen and nicotine patches, as a major area of pharmaceutical research. Dermatologists Peter Elias of the University of California, San Francisco, and Donald Downing at the A LITTLE GOES A LONG WAY: David Pisetsky of Duke Medical Center says that NIAMS does "first-rate" research with a small amount of funds. University of Iowa-extramural NIAMS grantees-are major contributors to studies of the barrier function of the skin. In basic skin science, "the area that's accounted for the most excitement in the last several years has been the ability to find the gene that is the basis of a number of hereditary skin diseases," remarks Moshell. "With the gene in hand, we can now find out how the gene defect results in disease. The hope is that that will lead to a better understanding of the disease process and possible interventions." Intramural scientists Peter Steinert, a biochemist who studies the structure of keratins, and Sherri Bale, an epidemiologist studying the familial genetic aspects of skin disease, have also contributed to understanding the hereditary basis of a host of skin disorders. The best understood is a group of diseases of type-7 collagen. Defects in this collagen gene disrupt formation of the skin's structure. Extramural grantees Ervin Epstein, Jr., a molecular geneticist at UC-San Francisco; cell biologist Dennis Roop at Baylor College of Medicine; and Elaine Fuchs, a molecular geneticist at the University of Chicago, are other noted researchers in this area. The institute also funds studies covering the scaffolding of the human body: the bones and muscles. In the bone-research area, there's "a lot of talk about the possibilities and promise for improving joint implants," says McGowan. Hip-replacement research, for example, is "an incredible success story that has changed the lives of many people from painful and inactive to active," she points out. This has spun off research interests in biologically compatible and longer-lived materials, primarily because people are living longer. McGowan views basic bone biology as the bridge linking and contributing to both orthopedics and metabolic bone diseases. "What we now know about osteoporosis in terms of prevention, treatment, and diagnosis has all come out of the basic relationship of the cells to the tissues. One may think of the skeleton as static, but in fact there is a dynamic cycle of bone remodeling throughout life." In the past 10 years, according to McGowan, there has been an increasing recognition "that a disease like osteoporosis-bone loss to a significant extent-is not a natural concomitant to aging." Because there are many early-life factors, such as diet and exercise, that impact on bone loss later in life, "this disease is amenable to prevention and intervention," she states. Regarding muscles, Henry Metzger, director of NIAMS intramural programs, says that cutting-edge work is taking place in the intramural laboratory of physical biology. For example, in the muscle biophysics section of this lab, headed by Leepo C. Yu, NIAMS scientists are using synchrotron X-ray diffraction to study the structure of muscle contraction at the molecular level. The largest share of NIAMS funding goes to research on arthritis and other rheumatic diseases. Within the NIAMS extramural program, for example, $65 million, or 32 percent of the total fiscal year 1995 extramural budget, was devoted to arthritis and related areas of study. Intramurally, according to Metzger, one "exciting" area of study is a genetic disease called familial Mediterranean fever, which involves a predisposition to periodic tissue inflammation. Daniel Kastner, chief of the intramural genetics section, is homing in on the gene that governs this disease. NIAMS's TOP 10 LISTThe National Institute of Arthritis and Musculoskeletal and Skin Diseases' 10 most-cited publications, 1990-1995 RANKPAPERTOTAL CITATIONS 1 A. Svetic, F.D. Finkleman, Y.C. Jian, C.W. Dieffenbach, D.E. Scott, K.F. McCarthy, A.D. Steinberg, W.C. Gause, "Cytokine gene- expression after in vivo primary immunization with goat antibody mouse IgD antibody," Journal of Immunology, 147:2391-97, 1991. 68 2 D. Hohl, U. Lichti, D. Breitkreutz, P.M. Steinert, D.R. Roop, "Transcription of the human loricrin gene in vitro is induced by calcium and cell-density and suppressed by retionic acid," Journal of Investigative Dermatology, 96:414-18, 1991. 45 3 E.M. Sternberg, J.R. Glowa, M.A. Smith, A.E. Calogero, S.J. Listwak, S. Aksentijevich, G.P. Chrousos, R.L. Wilder, P.W. Gold, "Corticotropin releasing hormone related behavorial and neuro- endocrine responses to stress in Lewis and Fischer rats," Brain Research, 570:54-60, 1992. 40 4 A.D. Steinberg, A.M. Krieg, M.F. Gourley, D.M. Klinman, "Theoretical and experimental approaches to generalized autoimmunity," Immunology Reviews, 118:129-63, 1990 39 5 G. Alber, L. Miller, C.L. Ja, N. Varinblank, 38 H. Metzger, "Structure-function relationships in the mast-cell high-affinity receptor for IgE-Role of the cytoplasmic domains and of the beta-subunit," Journal of Biological Chemistry, 266:2613-20, 1991. J. Immunol., 149:1477-87, 1992. 38 7 M.E. Joyce, S. Jingushi, M.E. Bolander, "Transforming growth factor-beta in the regulation of fracture repair," Orthopedic Clinics of North America, 21:199-204, 1990. F.W. Miller, S.F. Leitman, M.E. Cronin, J.E. Hicks, R.L. Leff, R. Wesley, D.D. Fraser, M. Dalakas, P.H. Plotz, "Controlled trial of plasma-exchange and leukapheresis and dermatomyositis," New England Journal of Medicine, 326:1380-4, 1992. 36 9 R.L. Leff, L.A. Love, F.W.Miller, S.J.Greenberg, E.A. Klein, M.C. Dalakas, P.H. Plotz, "Viruses in idiopathic myopathies: Absence of candidate viral genomes in muscle," Lancet, 339:1192-5, 1992. 33 10 P.M. Steinert, "Organization of coiled-coil molecules in native mouse keratin 1/keratin-10 intermediate filaments-Evidence for alternating rows of antiparallel in-register and antiparallel staggered molecules," Journal of Structural Biology, 107:157-74, 1991. 32 Source: Institute for Scientific Information's Science Citation Index The genetic basis for the control of autoimmune forms of arthritis and related autoimmune diseases-at least in a rodent model-is being tackled by scientists in the inflammatory joint diseases section, headed by Ronald Wilder. "They've come up with evidence in rodents that are particularly susceptible to experimentally induced arthritis," notes Metzger. "They are trying to identify which genes are coding for this and searching for human analogs." Other intramural arthritis research sections are looking at the basic cell biology of connective tissue, joints, and the immune system. The lymphocyte cell biology section, headed by John O'Shea, is involved in work with JAK kinases, a class of proteins important to the cellular signal-transduction pathway. Researchers in this lab study the role of lymphocyte activation, and how deficiency in either the kinase or regulation of the kinase can lead to immunodeficiency. Metzger's own lab-the chemical immunology section-studies the molecular mechanisms leading to cytokine gene expression. The area of lupus genetics-which is covered in large part by the NIAMS arthritis labs-is "exploding," according to Susana Serrate-Sztein, director of the extramural arthritis branch. Recent studies funded by NIAMS have started to reveal the hereditary aspects of lupus, an autoimmune disease in which a person's own antibodies turn on a myriad of organs, such as skin, muscles, and joints, as well as other parts of the body. IN-HOUSE INVESTIGATION: Intramural research at NIAMS includes basic and applied studies, notes Henry Metzger, intramural program chief. One manifestation of this explosion is a multicenter research effort led by Jane E. Salmon, a professor of medicine at the Hospital for Special Surgery in New York City. In the March 1 issue of the Journal of Clinical Investigation (97:1348-54, 1996), Salmon and colleagues report on their discovery of a gene associated with an increased risk of lupus nephritis in African Americans. This is a kidney disease related to the demise of the immune system associated with lupus. People with the condition have faulty genes that control the production of Fc receptors-proteins that normally destroy harmful molecules called immune complexes. The Fc-receptor gene of lupus nephritis patients is inefficient at attacking the complexes, causing their harmful buildup in the kidneys. LICKING LUPUS: The field of lupus genetics is taking off, says Susana Serrate-Sztein. an extramural branch chief. The institute has just funded a new registry and tissue bank to identify genes that determine overall lupus susceptibility. This project is directed by John Harley, a professor of immunology at the University of Oklahoma Health Sciences Center. The repository will store blood, cells, and DNA from individual family members, using genetic markers to look for possible lupus genes. Lupus is not just a genetic disease. Its determinants are also environmental and hormonal. Ninety percent of lupus patients are women. The disorder, which is three times more common in African-American women than in white women, strikes most often during childbearing years. Related to the hormonal aspects of lupus, NIAMS is funding the first clinical trial on the safety of estrogens for women with lupus. Currently, these women are advised not to take estrogen because physicians believe it will cause blood clots. But, according to clinical-trial codirectors Jill Buyon, a rheumatologist at the Hospital for Joint Diseases in New York and rheumatologist Michelle Petri at Johns Hopkins Hospital, the safety of estrogen and lupus is an issue that has not been resolved. The trial aims to settle this question, with the most significant benefits likely for older and younger lupus sufferers. If estrogen is safe, for young women it would mean an effective birth-control method; for postmenopausal women, it would mean the option of hormone-replacement therapy. Genetic, clinical, and epidemiological studies on multi-organ diseases such as lupus are the cornerstones of NIAMS research. NIAMS-supported investigators are looking forward to even more scientific discoveries and clinical trials on the multitude of diseases they cover during the remainder of the institute's anniversary year.

10-Year-Old Arthritis Institute Goes Beyond Aches And Pains Of Joints

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