Osteoarthritis (OA), the painful and often debilitating joint disease in which cartilage breaks down until it can no longer serve its function as a cushion between the bones, is the most common underlying condition of patients seeking treatment at Hospital for Special Surgery (HSS). While the symptoms of OA are well-known, scientists are still uncovering the root causes of the disease. In the late stages of OA, the best treatment remains joint replacement. But today’s active patients are developing OA symptoms at younger ages, and the prevalence of OA is expected to increase dramatically as the Baby Boomers age. A leading cause of disability in the United States, OA is one of the most urgent research challenges of twenty-first century medicine.
Staffed with the world’s best orthopedic surgeons, musculoskeletal-trained radiologists, biomedical engineers, and basic scientists, and with patients with a wide range of OA symptoms to learn from, HSS is uniquely situated to lead in OA research.
Steven Goldring, MD, Chief Scientific Officer and St. Giles Research Chair, explains that a multidisciplinary focus is necessary to face the complicated research challenges posed by OA. “OA affects every part of the joint: the bone, ligament, tendon, cartilage, and even the muscles surrounding the joint. You can’t think of it as just a cartilage disease. OA is really the failure of an organ.”
Mary Crow, MD, Benjamin M. Rosen Chair in Immunology and Inflammation Research, is a senior scientist and rheumatologist who will soon step into the leadership role of Physician-in-Chief and Chair of the Division of Rheumatology. Dr. Crow is renowned for her scientific contributions to autoimmune disease research and rheumatology, and her translation of this research to patient care. Along with colleagues Jenny Scott, PhD, and Steven Goldring, MD, she is also involved in multidisciplinary OA research, which evolved from her study of inflammation in systemic lupus erythematosus and rheumatoid arthritis. She is now testing the hypothesis that inflammatory cells are present in OA and might play a role in disease progression.
HSS scientists have been studying inflammation in the large membrane that lines the joints, called the synovium, in an attempt to learn whether inflammation contributes to joint damage as OA progresses and, if so, whether the factors that determine progression of OA can be defined. By examining samples of synovial tissue and joint fluid gathered from previous surgeries, Dr. Crow and Carla Scanzello, MD, PhD, a rheumatologist who recently completed her training at HSS, documented that certain inflammatory molecules were increased in the joints of patients who turned out to have early OA. In current research, Drs. Scott and Crow are investigating how molecules produced in the synovium might result in cartilage damage, and why some people develop more severe OA, while others develop milder symptoms.
The Hospital’s registry of patients undergoing anterior cruciate ligament (ACL) repairs benefits OA research. Initiated by the Sports Medicine Service, the registry includes clinical data collected from patients receiving this surgery. Because HSS performs over 800 ACL repairs each year, this database is expected to become an important source of information on the long-term outcomes for these patients. Members of the Sports Service, including Scott Rodeo, MD, Jo Hannafin, MD, PhD, and Russell Warren, MD, work with research staff and colleagues in the Hospital’s Research Division to analyze tissue from patients participating in the ACL Registry.
Scientists compare tissue from patients with simple ACL tears and more serious joint damage to determine cellular and genetic differences between the two groups. The Sports Medicine surgeons will follow patients over time, collecting clinical data on who develops OA. Scientists will then look for a connection between inflammation and other biologic processes occurring in the joints early on and the development and severity of OA later in life.
“We’re getting closer to predicting the progression of OA, and to relating those clinical outcomes to a biologic process that we can understand,” Dr. Crow says. “The goal is to develop approaches to interrupting disease progression.
“It’s likely that there are many contributing factors to who goes on to develop severe OA. Some of those contributors will be the severity of the injury, and some contributors will be genetic. Some people respond to the same injury with more inflammation than others,” Dr. Crow explains. “So what determines the difference between different people? And what can that teach us about therapies that might prevent serious progression of this disease?” These are just some of the questions being asked at HSS.
Senior Scientist Mary Goldring, PhD, the Ira W. DeCamp Fellow in Musculoskeletal Genetics and Director of the Laboratory for Cartilage Biology in the Tissue Engineering Repair & Regeneration Program at HSS, specializes in the study of cartilage tissue research, specifically chondrocytes, the cells within the cartilage tissue. Dr. Goldring and her laboratory collaborators also work with Thomas Sculco, MD, Surgeon-in-Chief and Korein-Wilson Professor of Orthopedic Surgery, and members of the Arthroplasty Service, to obtain tissue samples from patients undergoing joint replacement, from which they investigate genes that play a role in the regulation of cartilage degradation and repair.
This work is critical to understanding the onset and progression of OA. Because cartilage has no blood vessels, it has little capacity to remodel in response to healthy loads across the joint or to heal when it is damaged by injury or disease. When cartilage breaks down, it cannot rebuild itself.
Dr. Goldring says, “the idea is to understand the very basic cellular mechanisms that lead to problems. If we understand the basic mechanisms involved in cartilage injury and repair, we may be able to define cellular targets for treatment and develop effective therapies.”
One particular challenge in OA research is that the disease begins before a patient feels any symptoms. Once new therapies are developed, patients may well need to be screened early on to fully benefit from treatment. To address this problem, skilled orthopedic radiologists and biomechanical engineers at HSS are already developing new ways to diagnose cartilage breakdown early in the disease process.
Hollis Potter, MD, Chief, Division of Magnetic Resonance Imaging in the Department of Radiology and Imaging and Director of Radiology and Imaging Research at HSS, specializes in musculoskeletal magnetic resonance (MR) research. She and her colleagues have developed techniques to non-invasively examine cartilage tissue. An MRI is essentially “a visual, objective, non-invasive microscope,” Dr. Potter explains. In the recent past, a surgical biopsy would have been required to diagnose disease in cartilage tissue. Now, MRI images can show if the cartilage is healthy.
MR can also objectively test new therapies. The FDA is increasingly requiring drug companies to use MR as a tool to assess the outcomes of new medications. “At HSS, we do clinically relevant research that will ultimately have an impact on patients’ lives,” says Dr. Potter.
With support from an NIH grant included in the American Recovery and Reinvention Act of 2009, Dr. Potter, her co-Principal Investigator biomedical engineer Matthew Koff, PhD, and other scientists are exploring another important fibrocartilage tissue in the knee joint called the meniscus. By correlating MR images with the biomechanical and biochemical properties throughout the meniscus, Dr. Potter and her colleagues are building a predictive model to determine when patients will begin to lose function in this important load-carrying structure.
The ability to measure cartilage health through MRI is a boon for OA research. Cartilage damage can be detected long before symptoms are felt. Because meniscal transplants will fail if the articular cartilage is too worn, cartilage imaging helps surgeons determine when a transplant is necessary and also objectively measures when a meniscus is fully healed after surgery.
In this study and others, the role of the Hospital’s biomechanical engineers, who apply the principles of engineering to study the effects of loads on the skeletal system, is integral to OA research at HSS. Working with radiologists and surgeons, HSS engineers examine how injury affects the structure and function of the skeletal system, and help figure out why injury is a risk factor for developing OA.
Howard Hillstrom, PhD, is a biomedical engineer and Director of the Motion Analysis Lab at HSS, whose engineers, technologists, physical therapists and physician researchers conduct a wide range of studies on OA from the perspective of structure (body alignment) and function (e.g., standing and walking). Dr. Hillstrom explains that “we’re interested in how OA affects the neuromusculoskeletal system in terms of pain and function, and how treatments aimed to conservatively (i.e., with a brace) or surgically realign limbs can improve clinical outcomes.” Physicians and physical therapists refer patients to the Motion Analysis Lab for comprehensive evaluations of how their bodies move in the context of their condition, physical limitations or disability. This information makes it possible for the medical team to devise the best, most personalized plan of treatment for each patient.
The lab, filled with high-tech electronic equipment, investigates mechanical factors that may play a role in the development of OA. Researchers study anatomy by measuring what happens to the body when it moves, with the goal of understanding how the relationships between joint alignment and body weight can influence the development of OA.
While still a fellow, Lisa Mandl, MD, MPH, a rheumatologist and recipient of the Charles L. Christian Research Fellowship at HSS, noticed that many patients suffered from basal thumb arthritis, a painful condition with few existing treatment options: non-steroidal anti-inflammatories, a cortisone shot, a splint, or surgery. Dr. Mandl is now involved with orthopedic surgeon Robert Hotchkiss, MD, Medical Director of Clinical Research and Director of Research for the Hand and Upper Extremity Service, as well as other HSS orthopedic surgeons and radiologists, in a randomized control trial to test whether an injection of a viscosupplement in the thumb (hyaluronan) will relieve symptoms without surgery.
Hyaluronan (HA) is a carbohydrate found in joint fluid. High levels of HA make the joint fluid a good lubricant and shock absorber. People with OA have lower levels of HA in their joint fluid. In this multidisciplinary study funded by the NIH, the Arthritis Foundation and an investigator-initiated grant from a maker of a hyaluronan product, HSS scientists investigate the efficacy of HA injections in the thumb. As part of this study and working with biomedical engineers in the Motion Analysis Lab and Cornell University, HSS scientists also use a specially designed device to measure treatment efficacy in the thumb.
The Hospital’s efforts in the area of OA are comprehensive. The research division supports clinical care areas by providing direct access to new research, including information about cartilage and inflammatory cells; the ability to identify early-stage OA in patients with sports injuries; and new treatments, braces, and prostheses. Regardless of their areas of specialization, HSS scientists share a commitment to helping our patients with OA, and people with OA around the world, move without pain.