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Publication Date March 2001Progress & Promise
NIAMS 15th Anniversary BookletTo be stewards of a biomedical research enterprise that affects the health of millions of people is a tremendous responsibility. For 15 years, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has been privileged to direct research against some of the world’s most chronic, costly, and common conditions: those affecting bones, joints, muscles, and skin. The rewards have been rich: a better understanding of the basic biology of these conditions, the transfer of knowledge from laboratory bench to patient bedside, and the nurture of scientists to carry on the work in the future.
As we take stock of where we have been, we invite you, our partners and stakeholders in research, to share these successes and peer into the future:
- You, the person challenged by disease, and your family and friends
- You, the organizations and associations that offer support
- You, the health care professional who diagnoses, treats, and counsels patients
- You, our National Institutes of Health colleague who collaborates with us
- You, the seasoned investigator who makes research happen
- You, the new scientist who wants to make a difference
- You, the decision maker who shapes the road ahead
- You, the taxpayer who supports the research.
As you read these pages, we hope you will catch the excitement about the discoveries of the past 15 years--and those yet to come!
- Arthritis and Other Rheumatic Diseases
- Osteoarthritis
- Rheumatoid Arthritis
- Juvenile Rheumatoid Arthritis
- Systemic Lupus Erythematosus
- Ankylosing Spondylitis
- Scleroderma
- Fibromyalgia
- Inherited Inflammatory Disorders
- The Skeletal System
- Osteoporosis
- Paget's Disease of Bone
- Bone and Cartilage Biology and Repair
- Total Joint Replacement
- Physical Rehabilitation
- Low Back Pain
- Sports and Exercise Physiology
- Connective Tissue
- Muscles
- Skin
- Skin as an Immunologic Organ
- Wound Healing and Treatment
- Skin as an Agent of Therapy
- Skin Cancer
- Heritable Skin Disorders
- Psoriasis
- Hair Loss
- Health Disparities
- Alternative Medicines
- The 21st Century
Arthritis and Other Rheumatic Diseases
Rheumatic diseases, which encompass the different forms of arthritis and scores of other disorders, are so called because they cause pain or stiffness in joints, muscles, or bones. Some are the result of the body’s immune system attacking its own healthy tissues, such as the joints and internal organs. Finding better treatments and eventual cures for these often debilitating diseases will require a better understanding of the diseases themselves.
Osteoarthritis (OA), the most common type of arthritis, affects cartilage, the tissue that cushions the ends of the bones within the joints. A major cause of pain and disability, OA occurs when cartilage wears away, leaving a bone-on-bone joint. Because prevalence of the disease increases with age, the graying of America’s population means that the number of OA cases is increasing as well.
Although there is no cure for OA and no proven way to stop the damage it causes to cartilage, we now have some tools to apply to cartilage breakdown and potential treatments:
An OA gene: a faulty collagen gene found in an inherited form of the disease. Collagen is the major protein-building material of bone.
A better understanding of how certain enzymes break down cartilage in the joints, which has led to experimental treatment.
The finding that antibiotics such as doxycycline inhibit the enzymes that degrade cartilage. One large study is evaluating the use of doxycycline for the prevention of knee OA in older women.
The discovery that bone density is increased in OA, suggesting that, in its early stages, OA may be a bone disease.
Studies of the disease in the U.S. population have also shown us that:
Running is not a risk factor for OA. Obesity, however, is.
The link between obesity and OA is more pronounced for African Americans than for Caucasians.
People who engage in more than 4 hours of heavy physical activity per day are seven times more likely (13 times, if obese) to develop knee OA than people who do no physical activity.
Women are two times more likely to have hand OA than men.
Women using oral estrogen, particularly those who have taken it for 10 years or more, have significantly reduced risk of hip OA.
Dietary intake of vitamin C, beta carotene, and vitamin E is associated with a reduced risk of cartilage loss and of disease progression in knee OA.
Doctors are recognizing that early diagnosis and treatment are needed to properly manage OA. This may be increasingly so as treatments are developed to halt cartilage breakdown. For this reason, NIAMS supports research to develop standardized, sensitive tests for OA-specific markers in body fluids or tissues. We hope that such tests will permit early diagnosis and detect subtle changes that occur with disease progression or effects of treatment.
We now know much more about what causes and continues the disease process and resulting joint damage in rheumatoid arthritis (RA), an inflammatory disorder of the joint lining. RA, an autoimmune disease, affects 2.5 times as many women as men. To fight RA, we can now rely on:
A better understanding of immune system problems in the disease process.
A rodent model of RA, which has helped explain how the neuroendocrine (hormonal) and immune systems interact in RA and other autoimmune diseases. Parallel studies of people with RA are examining whether similar interactions play a role in human disease.
An understanding of how enzymes called metalloproteinases help destroy joint tissues.
New ideas about why RA improves during pregnancy. One study has suggested that differences in certain proteins between a mother and her unborn child may change the activity of the mother’s immune system--a possible clue to new treatments.
Insights into how RA is affected by adhesion factors, which help inflammatory cells move from the bloodstream into affected tissue, and the formation of new blood vessels. Experimental animal treatments that impair these factors have been encouraging.
Increased evidence of genetic factors in RA. Scientists have identified two clusters of genes that may regulate susceptibility to many forms of autoimmune disease in rodents, including rheumatoid-like arthritis. They have also found six distinct genetic regions that control inflammatory arthritis in rodents, and discovered mutant genes in the tissue lining the joints of people with severe RA, suggesting the disease can progress independent of inflammatory elements.
A whole new class of drugs, called biologic response modifiers, has been developed to treat RA. Two of them, etanercept (Enbrel*) and infliximab (Remicade*), have been approved by the Food and Drug Administration, and are already making a tremendous difference in patients’ lives today.
A number of other studies supported by the NIAMS have demonstrated the effectiveness of other RA treatments, including clinical studies showing that:
Low-dose methotrexate is effective in adults.
Minocycline reduces joint pain and swelling and is safe for patients with mild to moderate RA.
New and ongoing NIAMS-supported research has the potential to increase our understanding of and improve treatments for RA. Examples are:
A multicenter clinical trial of a small peptide given orally to treat RA.
A project to see why certain anti-inflammatory proteins do not reduce inflammation of the joint lining.
A study of mechanisms that lead to abnormal growth patterns in the cells lining the joints.
A project involving live imaging of tiny blood vessels in animal models of RA.
* Brand names included in this document are provided as examples only, and their inclusion does not mean that these products are endorsed by the National Institutes of Health or any other Government agency. Also, if a particular brand name is not mentioned, this does not mean or imply that the product is unsatisfactory.
Similar to adult RA, juvenile rheumatoid arthritis (JRA) causes joint pain and inflammation and, sometimes, irreparable joint and organ damage in children and young adults. To help scientists understand more about this autoimmune disease, the NIAMS is sponsoring a research registry for juvenile rheumatoid arthritis at the Children’s Hospital Medical Center in Cincinnati. This registry focuses on families in which more than one child has JRA. Its goal is to find genes that increase susceptibility to JRA.
NIH has also opened its first pediatric rheumatology clinic at its own research hospital. The clinic, which will be conducted by the NIAMS, will diagnose, evaluate, and care for children with arthritis and other chronic rheumatic diseases and will expose doctors to pediatric rheumatology, an area that is greatly underserved.
Other NIAMS-supported studies have helped doctors test the effectiveness of new and existing drugs in JRA. Included are clinical studies showing that:
Low-dose methotrexate is safe and effective for treating JRA in children who do not respond to first-line therapies.
Etanercept (Enbrel) is a safe and effective drug for treating children and teenagers with polyarticular JRA, which affects more than four joints.
A potentially devastating autoimmune disease that affects women and minorities disproportionately, systemic lupus erythematosus (also known as SLE or lupus) can affect the joints as well as numerous organs and body systems, including the kidneys and cardiovascular and nervous systems. Not long ago, a diagnosis of lupus almost always meant a drastically shortened life span. However, lupus research--much of it supported by the NIAMS--has enabled people with lupus to live longer, healthier lives.
NIAMS-supported research has helped us better understand some factors and processes involved in lupus. We now know that genetic factors influence who gets
lupus and how severe the disease becomes. Scientists working in lupus genetics have found:
A gene linked to increased risk of lupus kidney disease in African Americans. Variations of this gene affect the ability of immune system cells to remove potentially harmful molecules from the body.
Two genetic risk factors in lupus: absence of the C4a gene and changes in the Fc receptor gene. Both of these genes are normally involved in removing immune system components that often settle in and damage the organs of people with lupus.
Genetic factors in animal models of lupus that could lead to strategies for altering the course of the disease.
Three genes that are important for normal immunity. This information could help us understand immune system abnormalities such as those seen in lupus.
Seven to 10 regions of DNA that are linked to lupus in mouse models, which suggests that lupus susceptibility genes may be similar in mice and people.
Evidence that differences in structure between bacterial and vertebrate DNA can be relevant to their different effects on the immune system. Certain bacterial DNA may promote the development of lupus.
An association between lupus and a gene region on chromosome 1.
Other researchers have studied the disease process and discovered:
That infectious agents and other environmental factors help trigger disease in genetically susceptible people.
Data suggesting that lupus may involve defects in programmed cell death, a normal process by which the body gets rid of unnecessary, damaged, or potentially harmful cells.
A better understanding of how two specific autoantibodies, proteins that react against the body itself, contribute to miscarriage and other complications of lupus.
Knowing more about the underlying mechanisms of lupus is already leading to experimental treatments, including the so-called biologic therapies involving substances that occur naturally in the body. Major treatment successes from the NIAMS Intramural Research Program include immunosuppressive drugs (cyclophosphamide and prednisone) that can prevent or delay kidney failure due to nephritis, the most serious common complication of this disease. These drugs restrain an overactive immune system by blocking or curbing production of some immune cells. Other therapies are showing promise in delaying or halting kidney disease in animal models of lupus.
Further NIAMS research has revealed that:
Lupus disease activity and health status are strongly associated with potentially modifiable psychosocial factors, such as a patient’s attitude about participating in the management of his or her own disease.
Hispanic and African American people have lupus in higher numbers than non-Hispanic white people, and they have more severe disease at the time of presentation.
Genetic and ethnic factors seem to be more important than socioeconomic factors in influencing disease activity when it begins.
Ankylosing spondylitis (AS) is an inflammatory form of arthritis that affects the spine as well as some peripheral joints. In the most severe cases of the disease, tissues that support the spine can become bone-like, causing the spine to stiffen and fuse in one position. A major step in AS research came in 1999 when the NIAMS established the North American Spondylitis Consortium, which will search for genes that determine susceptibility to the disease. By collecting and studying medical information and genetic material from 400 families in which two or more siblings have AS, researchers hope to learn more about genes that play a role in this condition.
Scientists working on AS have discovered:
That both a bacterial trigger and genetic susceptibility are needed for the disease to occur.
That AS shares a genetic marker with Reiter’s syndrome, a disorder whose symptoms include arthritis, eye redness, and urinary tract problems. Scientists suspect that protein binding to this marker alters the body’s normal immune response, resulting in one of the two diseases.
A rodent model for AS that carries the human HLA-B27 gene, one known to be common in people with AS. The model has shown that this gene could lead to joint inflammation and other symptoms characteristic of this form of arthritis in humans.
The NIAMS also sponsored a major scientific conference on AS in 1998 to review the state of research on the disease and to promote new ideas and approaches to its study.
Scleroderma is a group of diseases involving abnormal growth of connective tissue, which supports the skin and internal organs. A potentially disfiguring and debilitating disease, scleroderma (literally, “hard skin”) results from a buildup of the protein collagen in the skin, blood vessels, and sometimes internal organs. It is not well understood, but NIAMS-supported research has provided some new clues into the potential causes and processes in this disease. Among the highlights are:
The identification of a chromosomal site associated with scleroderma in Oklahoma Choctaw Native Americans. This suggests that the gene for a protein called fibrillin-1 is a possible susceptibility gene for scleroderma.
Finding lingering fetal cells in skin lesions and blood of women with scleroderma who had been pregnant years before developing the disease. This may mean that an immune reaction may be behind the disease in some people.
The discovery that cells from people with scleroderma have twice as many receptors for a molecule called TGFb than do cells from people without scleroderma. The binding of the chemical TGF to the receptors signals a cell to produce collagen, which is overabundant in people with scleroderma.
New and ongoing research into scleroderma includes:
A study looking at the roles of blood vessel malfunction, cell death, and autoimmunity in scleroderma.
A multicenter clinical trial testing the value of orally administering collagen peptides to people with scleroderma.
A study of differences in the structure and organization of tissue fibers in people with scleroderma.
Fibromyalgia is a chronic disorder predominantly affecting women, and is characterized by widespread pain and fatigue. Other common problems include abdominal pain, bloating and constipation and/or diarrhea, migraine headaches, sleeping difficulties, and problems with concentration.
Although the condition and its cause--and optimal treatment--are not well understood, NIAMS-supported research is starting to make headway in uncovering the fundamental disease mechanisms. For example, one NIAMS-supported study found that brain scans of people with fibromyalgia showed significantly lower blood flow than those of unaffected people. This suggests that brain structures involved in pain perception may have a functional problem in people with fibromyalgia that accounts in part for lower pain thresholds. Knowing this could help scientists target better interventions.
Funding of fibromyalgia grants has increased dramatically in recent years, and investigations cover broader areas. Current NIAMS-funded projects include:
Analyzing genetic linkage in 120 families with fibromyalgia.
Examining the link between stress reactivity and pain sensitivity in fibromyalgia patients, and comparing the data with findings from patients with temporomandibular joint disorder and people who have no pain.
Developing a rat model of fibromyalgia pain.
Comparing the relationship of pain sensitivity to clinical outcome and other factors in fibromyalgia and low back pain.
Seeing whether aerobic exercise helps patients with fibromyalgia through stimulation of the pituitary and adrenal glands.
Developing a new model of pain that is both chronic and widespread, and then determining if this model involves the peripheral or central nervous system.
Examining the risk factors associated with temporomandibular joint disorder and fibromyalgia in young women.
Testing whether cognitive behavioral therapy will improve insomnia in people with fibromyalgia.
Inherited Inflammatory Disorders
In the mid-90s, NIAMS intramural researchers identified the gene for familial Mediterranean fever (FMF), a hereditary disorder common among people of Jewish, Arab, Armenian, and Turkish ancestry. FMF’s symptoms can include fever, abdominal and chest pain, arthritis, and skin rashes. The gene holds the code for making the protein pyrin, which is thought to help keep inflammation under control. Mutations in the gene lead to a malfunctioning protein and uncontrolled inflammation. The discovery of the gene has already facilitated development of a simple diagnostic blood test for FMF, and it will provide insight into causes of inflammation and better treatments for FMF and perhaps other diseases characterized by inflammation.
NIAMS scientists and their collaborators also discovered genetic mutations on chromosome 12 underlying a newly recognized group of inherited inflammatory disorders, collectively known as TNF receptor-associated periodic syndrome (TRAPS). These disorders, which are similar to familial Mediterranean fever, are characterized by long, dramatic episodes of high fever; severe pain in the abdomen, chest, or joints; and skin rash and inflammation in or around the eyes.The mutations affect the inflammatory protein tumor necrosis factor (TNF), and are important in understanding the role of the TNF pathway in disease. The discovery could potentially lead to additional treatments at the cellular level for many immune-related and inflammatory disorders.
Our bones, joints, and cartilage give us a living framework upon which all the other systems of our body depend. They are marvelously constructed to give us strength, protection, stability, and mobility. We sometimes forget that this skeletal system is composed of active cells, and is subject to metabolic and genetic processes, trauma, and the gradual wear and tear of life. NIAMS-supported research has helped millions address the problems that can result, often improving quality of life.
Osteoporosis is a common condition, primarily of women and people in their later years, in which the bones lose mass, making them vulnerable to fracture under the slightest trauma. Today, an explosion in knowledge about how bone-forming and bone-resorbing cells work and how they are regulated by hormones, growth factors, and drugs has laid the groundwork for new treatments. Scientists have made great strides in the following areas:
Bone Cells. Scientists have learned much about how bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts) work and how they are regulated by hormones, growth factors, and drugs. Certain agents can interfere with osteoclast function and prevent bone loss. The hormone estrogen affects bone by inducing programmed cell death in osteoclasts. Improper levels of parathyroid hormone-related peptide (PTHrP) are linked to serious bone mass problems, pointing to the potential of using targeted therapies against PTHrP to preserve bone. Finally, a protein called Cbfa1 has been discovered to be a "master switch" for bone formation, and several genes with links to osteoporosis have been found.
Glucocorticoid-Induced Osteoporosis. An important risk factor for osteoporosis is using glucocorticoid drugs to prevent organ transplant rejection or to treat inflammatory diseases. NIAMS-supported investigators used a mouse model and cell culture techniques to shed new light on glucocorticoids' destructive mechanism and to point the way to preventive measures. They found that mice treated with the glucocorticoid prednisolone have bone loss similar to that seen in people and had reduced numbers of bone-forming osteoblasts. Glucocorticoids also reduced the rate of osteoblast formation in cultures of mouse bone marrow cells.
Osteoporosis Risk Factors. Increased understanding of the causes of and risk factors for osteoporosis is enabling doctors to identify patients at high risk for developing the disease and to take steps to reduce that risk. Scientists have found that increasing age and low body weight are two of the most important risk factors, and that drugs that act on the mind and failing visual ability contribute to osteoporotic fractures by increasing falls. They have also discovered that the risk of certain osteoporotic fractures may be partially rooted in a gene on chromosome 19. The Study of Osteoporotic Fractures has helped define osteoporosis--and identify individuals at risk for fracture--using bone mineral density measurements at the hip.
Osteoporosis in Men. Although osteoporosis is often considered a disease of women, it is becoming an increasingly significant problem among men as life expectancy increases. The Institute is supporting a seven-center, seven-year study following some 5,700 men 65 years and older to determine the extent to which the risk of fracture in men is related to bone mass and structure, biochemistry, lifestyle, tendency to fall, and other factors. Researchers have found that low body weight, difficulty walking, use of certain medications, and smoking are risk factors for hip fracture in men. They have also discovered the importance of estrogen to bone mass in men.
Treatment and Prevention. Research findings are already leading to clinical applications for many people. Institute-supported investigators have found that supplemental calcium prevents spinal fractures in elderly women, but that replacing the male hormone testosterone does little to increase bone growth in most older men with bone loss. Exercise and hormone replacement therapy (HRT) work together to prevent bone loss in postmenopausal women, and giving lower doses of estrogen and progesterone during HRT, in combination with calcium and vitamin D, spares older women significant bone loss while limiting HRT's serious side effects. Other important clinical research has led to technologies to assess bone density and bone quality, including dual-energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and quantitative ultrasound measurement. New biochemical markers of bone metabolism have been discovered, and tests for these markers are becoming quick, simple, and highly cost-effective ways to identify bone loss and monitor therapy.
Paget's disease is a serious, chronic skeletal disorder that may result in large, malformed, and fragile bones. Although the exact cause is not known, particles from certain viruses have been found in bone-resorbing cells in people with the disease. This finding has led to a model in which infection with slow-acting viruses affects disease development. Several other lines of study indicate that Paget's disease has a genetic component, suggesting that a genetic predisposition interacts with environmental triggers like viral infection to produce the disorder.
Scientists have also found that interleukin-6, a hormone-like chemical messenger, helps promote the overactivity of osteoclasts in people with the disease. Further understanding of the causes of the disease will allow more targeted treatment and perhaps prevention.
Bone and Cartilage Biology and Repair
Research advances in the basic biology of bone and cartilage are the lifeblood of the clinical trials from which treatments emerge. The discovery of bone morphogenic proteins, which regulate bone growth and repair, and other insights into the molecular mechanisms of bone and cartilage are leading to:
Ways to improve the rate of fracture healing, as well as the strength of the healed bone.
Advances in bone grafting and implantation methods to replace large segments of bone lost as a result of trauma or tumor surgery.
Experimental methods to generate new cartilage or use biologic agents to drive repair of cartilage in the joints. Such techniques can be used in cases where cartilage is damaged in arthritis or by injury.
Furthermore, cartilage biology investigators have discovered:
That nitric oxide may promote cartilage damage in osteoarthritis and that controlling nitric oxide may prevent this damage.
A mechanism by which cartilage cells die.
A growth factor called human osteogenic protein 1 that is produced by cartilage cells in people of all ages. This protein may be useful in helping to form cartilage in people with osteoarthritis.
When arthritis becomes so severe that drugs will not relieve the pain or when joint problems make daily activities painful, difficult, or even impossible, doctors can sometimes replace the damaged joint with an artificial one. Improvements in materials and techniques have increased the quality of life for many people, making it possible for the elderly and young people alike to live independently. NIAMS-supported research has also found that total hip replacement becomes increasingly cost-effective as people age.
While most studies confirm the benefits of total joint replacement both to the patient and society, there are still concerns about the effects of the implant on the body and how long the implant will last. The following advances will likely have an impact on future implant quality and longevity:
Better understanding of how artificial joint materials interact with the body. This will result in new materials that can reduce the chance that artificial joints will trigger wearing of nearby bone and loosening of the implant.
In-vitro models to study the effects of different wear particles, including titanium and polystyrene, on bone collagen.
The discovery that tumor necrosis factor (TNF) is an essential ingredient in wear particle-induced osteolysis, the virtual disappearance of bone around an implant.
Contrary to traditional belief, research shows that prolonged rest after ligament or tendon injury only leads to further degeneration of the injured tissue. Carefully designed exercise and use of the injured tissue, on the other hand, actually help its repair. These and other findings of NIAMS-supported research have improved the clinical view of rehabilitation in recent years, leading to better, faster, and more cost-effective care.
At some point in their lives, most Americans will develop back pain. For some, the cause will be simple muscle strain that eases in a matter of days. But for others, the cause will be more complex and the problem lingering, affecting the ability to work or handle daily activities.
NIAMS-supported researchers have had success in understanding the biomechanics of the spine and of low back pain and back injury. They have:
Developed ways to study the effects of various tasks on loading of the spine. One study showed that certain twisting motions can cause or aggravate back injury. Knowing this makes it possible to train people in the best ways to do their work while avoiding back injury or aggravation of chronic back problems.
Looked at how a chemical called phospholipase A2 (PLA2) helps cause and perpetuate low back pain. Researchers saw that PLA2 release by injured disks (the spongy cushions between the vertebrae) may irritate the nerve roots. The resulting loss of nerve function may explain the loss of peripheral sensation in those with a history of pain radiating down the leg or into the buttocks. PLA2 could be a new target for the pharmacologic or biologic treatment of acute and chronic low back pain caused by a ruptured disk.
As an example of the Institute's commitment to back pain research, the NIAMS is supporting the study of surgical versus nonsurgical treatment of three back disorders in 1,450 patients at 11 medical centers. Scientists at these centers will compare these treatments in patients who have a herniated (bulging) lumbar disc, spinal stenosis (narrowing of the canal through which the spinal cord passes), or degenerative spondylolisthesis (in which a vertebra in the spine slips forward out of place). This project is expected to have a major impact on clinical practice and on the cost of medical services for low back pain.
Sports and Exercise Physiology
Sports injuries account for a growing number of emergency room visits as more people, particularly women, become physically active. The number of competitive athletes and regular exercisers at all skill levels has increased dramatically, as has the attendant injury rate.
The NIAMS has led the effort to better understand the basic biology of sports injuries and to better treat and prevent these injuries. Among its accomplishments are:
The sponsorship of a major scientific workshop to define what is known about women of all ages in sports and fitness. The workshop strove to profile the injuries prevalent in women, to highlight the most fruitful areas for research on their prevention and treatment, and to attract new investigators to conduct research on women's health in sports and exercise.
The discovery that differences in gene expression between the knee's anterior cruciate ligament (ACL) and medial collateral ligament (MCL) result in different rates of healing after injury. This could open avenues for using gene therapy to repair ligament injuries, especially those of the ACL.
The finding that a particular growth factor, bone morphogenetic protein-2, is important in repairing damaged articular cartilage. This information will help researchers better understand the molecular and cellular events in the process of replacing and reconstructing damaged tissue.
Connective tissue is the material between cells that gives the body and its organs form and strength. This "cellular glue" is made up of dozens of proteins whose production can be altered by genetic malfunction. Such genetic alterations can result in more than 200 heritable disorders of connective tissue (HDCTs), including Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome. HDCTs can affect skin, bones, joints, heart, blood vessels, lungs, eyes, and ears.
NIAMS-supported researchers have made great strides against these conditions, unraveling their causes, improving diagnosis, and opening the door to treatments.
In 1997, scientists created mice with a genetic condition that resembles Marfan syndrome, a potentially fatal condition that weakens tissues of the skeleton, eyes, lungs, heart, and blood vessels. These mice provided an unexpected new view of Marfan's connective tissue defects, especially aortic aneurysms (weak spots in the body's main artery, which can rupture under stress) that occur in people with the syndrome. The mouse model is valuable for understanding human disease and developing new treatments, and it may lead to insights about aortic aneurysms in general. Researchers are also matching gene mutations to clinical, cellular, and biochemical data to determine the normal functions of specific proteins like fibrillin-1, a major component of elastic fibers surrounding blood vessels. Such work should enhance understanding of the causes of Marfan syndrome and have an impact on both diagnosis and outlook for the disease.
Osteogenesis imperfecta (OI) results in brittle bones and leads to frequent fractures and, in many patients, to skeletal malformation. Most often, the underlying cause is a defect in the gene that regulates the production of collagen, which is essential for normal bone structure. In milder forms of OI, bone cells fail to synthesize normal amounts of collagen, while in more severe forms, mutations alter the structure of the collagen itself. Investigators found that certain mutations, though they involve only very small changes in the structure of the gene, block the production of the abnormal collagen. This may lead to a new treatment approach for severe forms of OI and could lead to a way to convert a severe form of OI into a milder form. NIAMS-supported research on OI continues to move forward with other projects ranging from cutting-edge gene and cell therapies to testing drug treatments in mouse models.
The characteristic feature of epidermolysis bullosa (EB) is extremely fragile skin that blisters easily with friction and sometimes even human touch. Scientists studying EB learned that a disruption of collagen production was responsible for separating the outer and inner layers of skin. They also identified genes and proteins underlying most of the hereditary forms of EB and found defects in a gene for keratin, the principal component of skin, in patients with EB. Through a NIAMS-supported EB registry, other researchers developed diagnostic methods and criteria for the various forms of the disease. It was also through the registry that a new technique using cultured skin cells was found suitable for wound healing for particular forms of EB. Today, EB is a prime candidate for gene therapy, and the NIAMS is supporting an effort to develop ways to deliver genes and animal and tissue culture models for testing, with plans to conduct a small clinical trial in EB patients.
Ehlers-Danlos syndrome (EDS) is a group of disorders whose hallmarks are stretchy skin, loose joints, fragile blood vessels, and abnormal scar formation and wound healing. The genes at fault are those involving collagen production. Investigators are looking at the molecular mechanisms by which mutations in the genes for collagen are expressed, and how collagen genes and proteins contribute to the assembly and function of the framework in which cells are embedded. Changes in the genes that affect the connective tissue protein elastin are also being studied, as well as how these abnormalities might affect EDS. An in-depth natural history study of EDS and other HDCTs should improve knowledge of their genetic origins, disease progression, and mutations in families.
Muscles do more than help weightlifters and marathon runners win trophies. We count on them for virtually everything we do, from carrying groceries to just being able to sit or stand, or even breathe. When muscles are worn or damaged through trauma, disease, or the aging process, the results can be devastating. One focus of NIAMS research is to better understand muscle function and how to preserve or improve it when problems arise. Scientists studying muscle have found:
The molecular structure of myosin, a muscle protein without which we could not move. This discovery is the result of 10 years of research support by the NIAMS. It helped to show how molecules in muscle convert chemical energy into force and motion.
More insights into muscle development, including how muscle gene expression helps transform undifferentiated embryonic cells into different muscle types.
Knowledge of how these processes work can help researchers understand what goes wrong when development is abnormal.That gene therapy can help the body fight the seemingly inevitable effects of aging or help repair damage caused by injury or muscle-wasting disorders. Using gene therapy in mice, NIH-supported scientists have been able to prevent the age-related decrease of muscle size and strength that leads to unsteadiness and impaired mobility.
Increased knowledge of the molecular signaling processes that control gene expression in developing muscle. This research aided the fields of both muscle development and developmental biology.
New information about the fundamental structure and function of skeletal muscle fibers, including the contributions of new muscle proteins. We now know better how muscles convert chemical energy into the force of muscle contraction, which helps us better comprehend diseases that affect muscles.
The muscular dystrophies are a group of inherited diseases characterized by muscle wasting and weakness. As our knowledge base of muscle biology expands,
NIAMS-supported investigators have been better able to understand the muscular dystrophies and provide hope for people challenged by them. These scientists
have:
Discovered that defects in a gene that expresses the protein dystrophin causes Duchenne muscular dystrophy (DMD), a form of the disease in which progressive muscle degeneration often results in death of affected boys by the age of 20. Researchers now hope to understand how defects in this gene cause disease, determine which parts of the protein are vital to protect muscle, and develop gene therapies.
Identified an animal model for DMD.
Found that dystrophin helps maintain the right levels of calcium in cells, without which muscles degenerate.
Discovered that applying the common antibiotic gentamicin restores the function of dystrophin in mouse models of DMD.
Investigated slow and fast muscle fibers and found that slow fibers are more resistant to the progressive muscle death that occurs in DMD.
Determined that gene therapy can restore muscle function in limb-girdle muscular dystrophy, a form of the disease in which muscles of the shoulders or pelvis are predominantly involved. Targeted gene therapy also has the potential to help people with other muscular dystrophies, including DMD, Becker (a form similar to, yet less severe than, DMD), myotonic (the most common form of muscular dystrophy in adults), and facioscapulohumeral (a rare form characterized by weakening muscles of the face, shoulder, and upper arm) muscular dystrophy.
People with myotonic and facioscapulohumeral dystrophy and their families are being helped by a new national research registry established by the NIAMS, where scientists seek out and classify patients with clinically diagnosed forms of these conditions and store their medical and family history data. The registry is also a central information source where researchers can obtain data for analysis.
Polymyositis and Dermatomyositis
Research on polymyositis, dermatomyositis, and related disorders--a group of autoimmune diseases characterized by inflammation and destroyed muscle--is benefiting from NIAMS support. Investigations have focused on:
The role of infectious agents, particularly viruses, in triggering the diseases.
The identification of disease-specific autoantibodies, proteins that attack healthy tissues.
The development of improved treatments.
NIAMS scientists studying inflammatory muscle disease have also discovered the genetic basis of several metabolic myopathies, disorders that closely mimic and so may be diagnosed as myositis. They have also created a mouse model of myositis that suggests a new theory of how the disease may develop.
Our largest and most highly visible organ, the skin, literally holds us together. And, like other organs, it is susceptible to disease, which can be disfiguring, debilitating, or even deadly. Among the major research focuses of the NIAMS are how skin functions, grows, and repairs itself, and how we can treat the diseases that affect it.
NIAMS-supported research has helped us gain insights into the normal and abnormal structure and function of the epidermis (the outermost layer of skin) and into the process by which cells in the epidermis develop their specialized structure and function. We have uncovered new proteins and determined how they maintain the integrity of the epidermis, which serves as a protective barrier against various attacks from the outside world.
Through research, we now have a radical new view of the skin as a complex and active immunologic organ. Scientists have identified several distinct cell types in skin that actively participate in generating, regulating, and perpetuating immune responses. These responses may occur only in the skin or may have more general manifestations throughout the body. Our new view of how the skin is affected by the immune system has implications for a number of important areas, including:
How ultraviolet (UV) light affects the immune system and the relation of UV light to skin cancer.
Our understanding of certain immune system cells in the skin.
The role of immune system components in the skin in the origins and development of AIDS.
Possible effects of ozone depletion, which reduces our protection from UV light, on the immune reaction to infectious organisms in the equatorial parts of the world.
The inability of certain wounds to heal in a timely fashion is the cause of great morbidity and mortality in the United States, particularly among the elderly, those on extended bed rest, and those suffering from conditions such as spinal cord injury and diabetes. The costs associated with chronic wounds have a major impact on the country. Since many of these wounds affect the aged population disproportionately, this problem will continue to grow as this group continues to increase in number.
Several different approaches have shown promise either in providing a better basic explanation for normal wound healing or in applying new agents and technology to the healing process. The NIAMS has been at the forefront of these advances, including:
Ways to grow skin in the laboratory, which will give doctors a new source of material for grafts.
The finding that a chemical related to vitamin D, called 1, 25-dihydroxyvitamin D, increases the rate of wound closure in the first 5 days after injury, with the greatest increase on day one. This study indicates that a potential new class of molecules may be effective in wound healing.
A model skin system that would allow a therapeutic gene to be put into skin cells to determine how useful gene transfer would be in healing chronic wounds. Although the gene transfer was effective only over short distances, the study established the model skin system as one in which preliminary testing can be done prior to application in human skin.
The discovery that increasing oxygen supply to wounded tissue may help improve healing responses.
Skin is uniquely suited for gene therapy approaches to disease, not just for skin disorders, but for other diseases as well. It is accessible, it provides a way to introduce genetic material using carriers other than viruses, and it can help produce molecules such as insulin and human growth hormone to treat systemic diseases. In addition, genetically altered skin can be simply removed if problems develop. The following advances show the pace of research in this area:
Gene therapy via injection improved the condition of an immune-deficient mouse model of basal cell skin cancer. This success could affect nonsurgical treatment of this most common human cancer in the U.S.
A NIAMS-supported conference increased the level of interest in the field of skin-mediated gene therapy and identified scientific opportunities and needs in this area.
The design of drug delivery systems that allow slow release of medications through the skin has made it possible to deliver certain treatments through means such as skin patches.
Important advances in human basal cell carcinoma, the most common form of skin cancer, and other forms of skin cancer are making these diseases highly treatable.
Among these successes are:
A mouse model of human basal cell carcinoma that will not only help doctors better understand the disease, but also help develop and test new treatments for it.
A class of medications called cyclooxygenase-2 (COX-2) inhibitors that reduce tumors in mice with a form of skin cancer called squamous cell carcinoma.
The discovery that certain gene mutations are likely to cause both basal cell nevus syndrome, a rare inherited skin disorder, and acquired basal cell carcinoma of the skin.
The finding that PUVA (the drug psoralen plus ultraviolet A light) used to treat psoriasis and other skin diseases increases the risk of melanoma and the risk of squamous cell cancers on male genitalia.
The discovery that PUVA can initiate melanoma and basal and squamous cell cancer in the same way sunlight does.
An animal model with potential use for studying basal cell skin cancers.
Researchers have found specific genetic defects that cause inherited disorders affecting the structural integrity of the skin. These disorders include the ichthyoses, a group of scaling skin disorders. The discoveries are resulting in more specific diagnostic tests, making possible prenatal diagnosis and genetic counseling, as well as opening the door to treatments, including gene therapy, to correct these defects. Scientists have:
Identified a gene mutation linked to the region of chromosome 1 that is likely to impair normal epidermal differentiation. This study demonstrated the power of genetic analyses in evaluating rare diseases. As researchers develop a better understanding of epidermal differentiation, insights into more specific diagnoses and treatments of disease are expected to follow.
Shown that a protein involved in developing the outer layer of skin is reduced in people with ichthyosis vulgaris, the most common form of the disease.
Discovered that lamellar ichthyosis, characterized by severe scaling that greatly affects a person's ability to sweat, is caused by mutations in the gene that regulates the protein transglutaminase 1.
Recent investigations have also led to a major change in how researchers view psoriasis, a chronic skin disease that generally appears as patches of raised red skin covered by a flaky white buildup. Most researchers now see psoriasis as an immunologic disorder rather than a disorder of keratinocytes, the primary type of cells in the outer layer of skin.
New treatments for psoriasis, including cyclosporine A and other therapies, work by modulating immune system function. Progress is also being made in identifying genes linked to psoriasis. Scientists have determined that, at least in some forms of hereditary psoriasis, there is a linked gene located on chromosome 17q. Once the specific genes for psoriasis have been isolated and their products determined, greater insights into the disease process will be available. This can be expected to open new avenues for intervention and improve treatment for psoriasis.
Loss of hair can be caused by a number of factors, including exposure to radiation or drugs that suppress the immune system. It can also result from a disease such as alopecia areata, an autoimmune condition that targets hair follicles. Researchers are making strides in understanding how hair grows and is lost, and they are applying that knowledge to treat disease.
Recent research has resulted in:
A mouse model with reversible hair loss that resembles human alopecia areata. Scientists have also identified autoantibodies to hair follicles in these mice.
The uncovering of the molecular bases of several human hair diseases.
Animal models for hair disease and the molecular mechanisms of various aspects of the hair cycle.
The localizing and mapping of the gene for atrichia, a rare hereditary loss of hair in humans, to chromosome 8.
The finding that the molecule beta-catenin is involved in the development of hair follicles. When beta-catenin was inserted into epidermal cells of genetically altered mouse skin, the skin underwent a process resembling new hair development. This finding indicates that it may be possible to form new hair in adult animals.
Evidence that a common stem cell produces both hair cells and constantly renewing skin cells. This opens an avenue for possible stem cell therapy for some skin conditions.
Arthritis and musculoskeletal and skin conditions are among the most frequent chronic health problems in the U.S., but not all population groups are equally affected. There are marked differences in the prevalence, morbidity, and disability associated with specific diseases in African American, Hispanic, Native American, and Caucasian populations. For some conditions, such as lupus and scleroderma, the burden is greatest in certain ethnic populations.
The NIAMS has been striving to reduce health disparities and to increase quality and years of healthy life for all segments of the American public. Notable in its efforts have been:
The launch of the Health Partnership Program, which addresses health disparities in joint, muscle, bone, and skin diseases that exist in minority communities. The initial phase has begun as a model program in the African American community in the metropolitan Washington, D.C., area, with the focus on rheumatic diseases. The program concentrates on four key areas: public health education, patient care, access to clinical investigations, and recruitment to research careers.
The hosting of a major scientific conference to review health disparities in arthritis and musculoskeletal and skin diseases and to promote new approaches to eliminating these disparities in ethnic groups at increased risk.
Support for studies such as lupus in minority populations and scleroderma in Native Americans.
Alternative therapies have always interested the American public, particularly those people who have chronic diseases studied by the NIAMS. With the recent establishment of the National Center for Complementary and Alternative Medicine (NCCAM), NIH and its member institutes have accelerated the pace of clinical testing for some of these therapies.
In collaboration with the NIAMS, for example, NCCAM funded the first U.S. multicenter study to investigate the dietary supplements glucosamine and chondroitin for knee osteoarthritis. A 4-year research contract was awarded to coordinate a nine-center effort to study the effectiveness of these two natural substances found in and around cartilage cells. The goal is to determine the effectiveness of glucosamine and chondroitin in reducing pain and improving function in patients with osteoarthritis of the knee. The hope is that the results will provide solid evidence of the benefits and safety of this treatment and help to expand health care options for patients affected by this major public health challenge.
In other research on alternative medicines, scientists have reported that green tea products show anti-inflammatory activity in mouse models. Rheumatoid arthritis is an example of an inflammatory condition affecting joints, resulting in pain and, over time, destruction of joints. In a recent study, investigators fed an antioxidant-rich organic substance isolated from green tea to mice before inducing inflammatory arthritis in them. They found that mice fed green tea products were significantly less susceptible to the development of inflammatory arthritis when compared to mice not fed these products. This research suggests that common dietary substances that can protect against or modulate the onset and severity of arthritis may be used in the future to treat or prevent rheumatoid arthritis.
Bones, muscles, joints, and skin are central components of the human body. Since the NIAMS was formed 15 years ago, we have witnessed the unfolding of new knowledge: how these components develop and function normally; how they are altered in disease; what roles genetics, the environment, and behavior may play; and perhaps most noteworthy, how disease might be prevented in the first place.
Ultimately, the conquest of disease always involves research across a broad spectrum--from basic to animal models to clinical trials to prevention research. In most cases, the essential ingredient is the translation: clinical research without the basic foundation is limited in scope and effectiveness, and basic research that is not translated into clinical studies misses the opportunity to improve public health. In the preceding pages, the interplay of many types and disciplines of research has resulted in stories of progress and promise that give us all hope.
We are now on the brink of discoveries that can revolutionize health care and the treatment of chronic illnesses. NIAMS-supported scientists are today uncovering important pieces of the research puzzle and are launching initiatives to take advantage of emerging areas of science. NIAMS research has ramifications for this generation and generations to come. We will continue to steward our Nation's investments in our future health, and American people of all ages and population groups will benefit from these investments.
NIH Publication No. 01-4939
March 2001
