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Osteoarthritis (OA), which is characterized by the gradual destruction of cartilage, is a major cause of pain and disability.

Yet, treatment options that modify the disease course remain limited. The major breakthroughs in OA have focused on the end stage of the disease, i.e., improved surgical techniques and synthetic materials to repair or replace joints that are already damaged.

Current medical therapies approved by the Food and Drug Administration for OA can provide symptomatic relief but do not stop the underlying cartilage loss and joint degeneration. But now there’s hope for a brighter future for the millions of individuals with OA, thanks to a special Arthritis Foundation osteoarthritis research program made possible by the extraordinary generosity of Gordon and Carole Segal, founders of the home furnishings retailer, Crate and Barrel.

In the early 1960’s, the Segals returned from their honeymoon and opened up a small store in a leased brick warehouse in Old Town Chicago. Today, due to their vision, personal involvement and willingness to take risks, their business is a growing enterprise with 130 stores nationwide. Gordon and Carole have brought the same positive qualities to their efforts to enhance the Arthritis Foundation’s OA research activities.

The Challenges

Four years ago, the Segals decided the time had come to stimulate innovative research that could change the outlook in OA. They talked to their family rheumatologist, Joe Golbus, MD and Jack Klippel, MD, then the Arthritis Foundation’s Medical Director, to learn about scientific opportunities and where their support could make a difference. They learned how difficult it is to detect early signs of OA and to assess the effectiveness of new therapies.

Currently the most widely used method to measure OA disease status is an X-ray to check for bone changes and the “joint space loss” or distance between the two bones in a joint, a marker for the amount of cartilage loss. However, X-rays have not been found to be very sensitive or reliable. On one hand, by the time there are visible X-ray changes, cartilage damage has usually occurred. It can take years to detect further progression or improvement—making it very time-consuming to assess whether a new treatment is effective. On the other hand, some people have severe OA symptoms without X-ray changes while others have X-ray changes with little or few symptoms. Joint space loss can also vary depending upon how the X-rays are taken.

So the search is on for more sensitive and valid methods to predict OA onset and progression, detect early signs of OA, follow disease progression and assess response to treatment. So-called “biomarkers” can include molecular markers found in blood and urine tests that can indicate early signs of cartilage breakdown or synthesis; early changes in cartilage volume or quality assessed through MRI scans or biomechanical tests; and genetic markers that can predict OA disease onset or progression.

The Solution: The OA Biomarkers Grant Program

The Segals made a significant financial commitment that made possible the creation of the OA Biomarkers Grant Program (OABIO). The program officially began in 2001 with the awarding of six grants that were aimed at identifying and testing of biomarkers.

Subsequently, the Segals’ continued generosity has allowed for the funding of eight more grants. In addition, they have continued their personal involvement in the program. After the National Institutes of Health implemented its OA biomarker initiative, the Segals were involved in the decision to expand the Arthritis Foundation’s program to support other meritorious OA research, including studies on how to rebuild damaged cartilage.

The Segals have also funded two symposiums to bring together the funded researchers, hear about their progress and provide a forum for exchange of ideas. As reported at the second annual Segal OA Symposium, hosted by the Segals and the Arthritis Foundation, Greater Chicago Chapter in June 2004, the funded scientists are pushing boundaries in the search for better ways to detect and monitor OA, more effective treatments and potential cures.

Read on to hear some highlights of this exciting research and progress. But first, to have a better context for learning about this research, we encourage you to read the sidebar to get a quick biology lesson.

Cartilage and OA

Cartilage is the hard and slippery cover on the end of the two bones in a joint that absorbs shock and reduces the friction between the bones. Cartilage consists of cells surrounded by a unique spongy structure called the extracellular matrix. The cells (chondrocytes) comprise less than 10% of cartilage volume and are responsible for synthesizing and maintaining the matrix. The large matrix component of cartilage is a meshwork of collagen fibers that provide strong tension, and interlocking protein and sugar chains called proteoglycans that bind large quantities of water. This structure, with its tightly bound water, gives cartilage its elasticity and ability to act like a “shock absorber.”

Cartilage doesn’t have its own blood supply, so it depends upon joint movement to obtain nutrition. The matrix acts like a “biologic sponge.” When the joint is moved, the cartilage is compressed and water and waste products are released. When the load is removed, the matrix reabsorbs water and other nutrients, allowing the cartilage to rebound to its original shape.

In OA, the normal balance between cartilage breakdown and synthesis is disrupted as the result of a complex interplay between cartilage and bone cells, mechanical forces and various molecules. The molecules that can affect this balance include hormones, growth factors, signaling proteins such as cytokines and integrins that serve as a relay system for communications between cells and the matrix, as well as many different types of harmful enzymes and their natural inhibitors.

As researchers have made more progress in identifying and characterizing these various factors, they are building the knowledge base that could lead to better ways to detect, treat and eventually prevent and cure OA.

Molecular Biomarkers

With an increased knowledge of cartilage biology, scientists have identified many molecular markers that are released into body fluids during the process of cartilage synthesis or breakdown. However, testing these to determine valid and reliable measures of OA disease activity has proved to be challenging. OABIO-funded researcher, Nancy Burton Wurster, PhD, at Cornell University has taken advantage of her laboratory’s unique resource—a large collection of greyhounds and Labrador Retrievers affected with hip dysplasia and OA.

Her team discovered high levels of cartilage breakdown products, including fibronectin and cartilage oligomeric protein (COMP) in the joint fluid of the osteoarthritic dogs. However, the range of levels obtained was too wide, limiting their diagnostic value. Undaunted, Wurster has now embarked on genetic studies in her families of dogs to help identify genetic markers that may be involved in the onset or progression of OA.

Leena Sharma, MD, another OABIO researcher from Northwestern University reported some success using a ratio that combines measures of two markers of collagen synthesis and breakdown. After examining 222 people with OA, she and her colleagues found that this ratio was better able to predict an increased likelihood of disease progression than the individual measures.

The Promise of Imaging

People with OA generally seek treatment after they have been experiencing severe pain or loss of function. At this point however, irreparable joint damage is usually already present. Recent developments in magnetic resonance imaging (MRI) could change this picture within the next several years. It is likely that routine clinical practice could include MRI scans to monitor cartilage health and the effects of treatment—similar to the way in which bone density testing is used in the management of osteoporosis.

As reported in the January-February issue of Research Update, another component of Dr. Sharma’s research is a collaboration with Dr. Deborah Burstein, PhD at Beth Israel Deaconess Medical Center in Boston to validate an MRI methodology called dGEMRIC that assesses the quality of cartilage by measuring the levels of proteoglycans, a major component of cartilage. This technique appears to be a very sensitive way to detect early changes that could lead to OA and to determine whether treatments are effective.

Dr. Shreyasee Amin, MD, MPH at Mayo Clinic, is another OABIO researcher exploring the value of MRIs. She and her colleagues at Boston University and UCSF are comparing the effectiveness of traditional X-rays and MRIs in evaluating knee OA progression in older adults over the span of 30 months. They have also been studying the relationship between cartilage loss and structural abnormalities seen on MRIs (such as bone changes and ligament tears). This research could help identify potentially modifiable factors that relate to disease progression and disability, and thereby help in the development of improved management strategies.

Biomechanical Aspects

Two OABIO researchers are using innovative bioengineering approaches to explore the role of mechanical factors in causing OA and to monitor the health of cartilage. Mechanical forces can “make or break” cartilage: while some degree of compression or load is necessary to get nutrition to cartilage, too much pressure, caused by obesity, repetitive forces or trauma, can contribute to the development of OA.

So can you quantify the levels of mechanical stimulation that are necessary for cartilage health vs. destruction? To answer this question, Kyriacos Athanasiou, PhD and Adrian Shieh, PhD at Rice University have developed a novel device and techniques to examine individual cartilage cells. With these tools now in place, they are characterizing the stiffness of single cells and how they respond to different levels of compression. They theorize that there may be critical thresholds of force that cause the cartilage cells to either express genes that lead to cartilage synthesis or its breakdown.

Knowledge gained from these experiments should increase understanding of the role of mechanical factors in causing OA as well as suggesting possible treatment options that stimulate cartilage repair.

Robert Sah, MD, ScD and his colleagues at the University of California at San Diego are testing an arthroscopic probe technique that objectively measures the stiffness of cartilage. They found that this “indentation technique” showed very early changes in cartilage and therefore may be a useful way to detect the severity of OA or to monitor the effectiveness of therapy.

Rebuilding Cartilage

Another important focus of the OABIO research program is innovative tissue engineering research—learning how to repair or grow new cartilage. Matthew Stewart, PhD at the University of Illinois at Urbana-Champaign is wrestling with why there is a loss of cartilage cells with aging and in OA. Fewer cartilage cells mean fewer “factories” to build and repair the cartilage matrix. He has discovered that when a certain gene called cyclin D1 is turned off, cartilage cells are not able to proliferate. He has also shown that cell growth can be restored, at least temporarily, by using a compound that increases cyclin D1 expression. Ultimately such research could lead to new methods to stimulate the growth of cartilage cells.

Similarly, William Horton, MD at Shriners Hospital for Children and the Oregon Health Science Center is trying to find the genetic factors that can speed up the process of turning stem cells obtained from bone marrow into cartilage cells. The insights gained from this research will help in the development of cellular therapy to repair cartilage defects and damage.

What’s Ahead

In closing the symposium, Gordon Segal expressed the pride that he and Carole feel about the OA research program. “We are so pleased with the important work being done. It is very gratifying to help get something new started and then watch it grow,” he said. The Segals have a continuing commitment to the program and hope that it will expand as others join with them to support this effort. The success of the OA program is an inspiring testament to the impact that individuals can make. The fruits of the Segal’s investment are already evident as new researchers have entered the OA field to answer critical questions. Adds Dr. Joe Golbus, “Undoubtedly, the Segal’s impact will be felt for years—as new insights found today lay the basis for future research discoveries that bring us closer to overcoming OA.”

Never doubt that a small group of thoughtful, committed citizens can change the world; indeed, it is the only thing that ever has. - Margaret Mead

Source: The Arthritis Foundation (online at www.arthritis.org).