This meeting brought together investigators with interests and experience in various aspects of osteoarthritis research—from basic science of cartilage to clinical interventions—to identify issues that are critical for current and future research related to the treatment and prevention of post-traumatic osteoarthritis (PTOA). Comparing perspectives from these points of view will help the NIAMS shape its plans and programmatic decisions. The breath of NIAMS interests in osteoarthritis research is illustrated by topics listed in the section on Musculoskeletal Biology and Diseases of the NIAMS Long-Range Plan: Fiscal Years 2010-2014 (http://www.niams.nih.gov/About-Us/Mission-and-Purpose/long-range.asp).
Osteoarthritis generally appears late in life, after decades of wear and tear and physiological responses. Joint trauma related to sports or other types of injury, for example, causes acute joint inflammation, cartilage damage, and significant increase in long-term risk for the development of osteoarthritis. However, how these injuries predispose patients to osteoarthritis is unclear. Treatment goals following traumatic joint injuries are: improvement of symptoms and function; restoration of structure; and prevention of osteoarthritis development and progression. Repairs of ligament and meniscal injuries are well-established procedures and usually restore joint function. However, they do not prevent the later (5-15 years) development of joint degeneration in 50-60 percent of patients. Studies focusing on joint changes immediately after injury offer opportunities to examine events leading to PTOA and to discern what constitutes a pathologic versus a healthy healing pathway. They also may provide insights into the extent to which injuries contribute to late-onset osteoarthritis.
Past national and international meetings focused on PTOA, such as the American Orthopaedic Society for Sports Medicine’s Post-Joint Injury Osteoarthritis Conference (December 2008). The Arthritis Foundation SNOW Conference (October 2009) also highlighted areas for additional PTOA research, including the development of post-injury treatments or protocols to improve outcomes for individuals with joint trauma and the identification of imaging and biochemical markers to predict early development of osteoarthritis in injured individuals.
State of the Science
Although surgical approaches to reattach torn ligaments, repair damaged menisci, and reassemble fragmented bones have become increasingly sophisticated, the improvements have not reduced the incidence of PTOA. While many researchers continue to explore strategies for restoring joint structure and biomechanical function, others are investigating pathological changes and natural healing processes that occur on cellular and molecular levels following injury.
Participants emphasized the importance of stratifying injuries when studying PTOA, as various types of trauma likely will initiate different degradation mechanisms. Compression injuries, for example, might produce osteoarthritis by a different mechanism than those that entail joint rotation and subject the chondrocytes on the cartilage surface to shear stress. Articular cartilage injuries also can be categorized as those in which the chondrocytes are damaged but the cartilage remains visibly intact, those that disrupt the integrity of the cartilage surface and may extend through the calcified zone, and those that are further complicated by damage to the surrounding tissue (e.g., joint dislocation or ligament tears). If the cartilage surface is not affected, therapies that could be administered early after injury to prevent additional damage may hold promise; if the cartilage is cracked, approaches that fill the fissures with biocompatible materials might spare the surrounding tissue from excessive mechanical stress. The location of the damaged cartilage also is important, as traumatic injury on non-load-bearing cartilage surfaces may trigger degradation elsewhere. In addition, differences in the thickness and tensile properties of the articular cartilage, such as in the ankle joint versus the knee, may result in variable responses to injury and differential development of PTOA.
Disease manifestations also vary. Some people may develop PTOA quickly, while the disease may progress more slowly in others. Studying the 40-50 percent of people who experience joint trauma but do not develop PTOA should provide insights into the behaviors (e.g., post-injury exercise), genetic factors, and molecular mechanisms that foster healing or protect joints. Anatomical differences between male and female joints, joints at various ages, and differences in joint integrity due to previous damage also may influence response to injury and progression of PTOA. Additionally, premature return to physical activity and subsequent re-injury appear to be triggers for earlier development of disease.
Diagnostic and Monitoring Strategies
At present, clinicians diagnose osteoarthritis from radiographic evidence and patient symptoms. They classify patients as having PTOA if the arthritis occurs in a joint that has suffered a prior injury and now has become symptomatic. Therefore, differences in how patients perceive and deal with pain profoundly influence whether someone with degenerative changes in joint cartilage is diagnosed, and how that person will respond to treatments. When designing studies and recruiting participants, researchers currently have no way of being certain whether a person developed osteoarthritis because of an earlier trauma or from a different cause. Moreover, clinicians cannot retrospectively ascertain the baseline, pre-injury status of an injured joint.
Researchers have developed and validated several tools for measuring physical performance (e.g., agility tests, kinematic assessments), but none can accurately determine the point at which patients can return to pre-injury levels of activity without an increased risk of additional injury. In the laboratory, researchers are using magnetic resonance imaging to assess cartilage health and detect early degeneration of cartilage in joints that eventually will develop osteoarthritis.
Development of methods for aligning and comparing magnetic resonance images for quantitative analysis (i.e., image registration methods) and appropriate metrics to assess cartilage integrity would allow researchers prospectively to monitor joints, and thereby determine which early changes are associated with later radiographic osteoarthritis. Some participants emphasized the importance of viewing data from magnetic resonance images as information that is distinct from x-ray findings. Unlike x-ray machines, the magnetic resonance equipment used in clinical research is not practical for daily patient care. Therefore, other tools that can be used to measure cartilage integrity would be valuable for detecting early stage PTOA.
Methods that are 100-fold more sensitive than magnetic resonance imaging also would be useful for studying PTOA at the cellular level. Engineers may be able to modify handheld confocal microscopes or optical coherence tomography equipment developed for other clinical purposes. Improvements in imaging could enhance the ability to test potential therapies in clinical studies. For example, researchers are investing considerable effort into preserving and restoring chondrocyte function and preventing cell death, but lack the ability to noninvasively monitor chondrocyte metabolism in humans.
Prevention and Treatment
The ability to observe changes in cell function and cartilage structure in intact joints could allow researchers to develop new hypotheses about the biochemistry underlying PTOA, and uncover biomarkers that will identify people who are at greatest risk of developing PTOA. Considering a broad spectrum of possible molecular markers would widen the community’s perspective on PTOA and elucidate the roles of cell damage in this process.
In addition to improved imaging methods, discussants expressed a need for animal models that are appropriate for preclinical safety and efficacy testing of potential treatments during drug development. Studies using genetically different mouse models could also inform understanding of the molecular mechanisms involved in development of PTOA and lead to identification of molecular markers.
Participants discussed the role of the synovial environment in chondroprotection, and whether intraarticular injections could prevent joint degradation. While excessive synovial inflammation causes patient discomfort, joint effusion is not necessarily associated with microscopic damage to cartilage. The balance between restorative and destructive inflammation following injury also is unclear, and needs to be considered when deciding to treat patients with anti-inflammatory drugs (e.g., glucocorticoids) after an injury.
Some data suggest that trauma alters the lubricating properties of synovial fluid. While viscosupplementation, such as injections of hyaluronic acid, may appear to improve joint function, at least in the short term, evidence supporting the practice is inconclusive. Studies of synovial fluid physiology and response to injury may reveal additional compounds, such as lubricin-like molecules or selected microRNAs, that could interact with cartilage and chondrocytes to facilitate healing or prevent further damage.
Other potential treatments include intraarticular injections or oral administration of antioxidants, caspase inhibitors, and nitric oxide mediators. Injectable gene therapy approaches are being tested in small animal models. Participants repeatedly noted that the effects of injectable or oral therapies are likely to be modest, and several approaches may need to be combined to prevent PTOA by targeting multiple pathways.
The timing of interventions is also likely to be important. Caspase inhibitors, which prevent apoptosis, are being studied as an initial treatment for injuries. Osteochondral grafting of visibly damaged cartilage currently is an option for some patients, but is most effective if done before PTOA becomes severe. Participants speculated that when effective preventive therapies are available and clinicians can predict which patients are likely to develop PTOA, the treatment paradigm will encourage immediate evaluation and medical care.
Patient behavior following an injury also remains an uncontrolled variable that may influence PTOA. Many patients adapt their biomechanics to avoid pain, but inadvertently adopt unhealthy movement patterns that may increase their risk of joint degradation. Some adaptations are so subtle that only sophisticated laboratory tools can alert clinicians that additional physical therapy is needed. Researchers also were interested in understanding the optimal level and type of physical activity during recovery. Because muscle strength is an important aspect of joint mechanics, physical therapy regimens that maintain or restore muscle function while allowing the injured cartilage and connective tissue to recover could delay PTOA.
For more information about this meeting or to discuss NIH support for research on this topic, contact Dr. Gayle Lester (email@example.com; 301-594-5055) or Dr. James Panagis (firstname.lastname@example.org; 301-594-5055).
- Joseph A. Buckwalter, M.S., M.D., University of Iowa Hospitals and Clinics
- Constance R. Chu, M.D., University of Pittsburgh
- Anthony E. "AJ" Johnson, M.D., MAJ(P), M.C., U.S. Army, San Antonio Military Medical at Fort Sam Houston
- C. Kent Kwoh, M.D., University of Pittsburgh
- Hollis G. Potter, M.D., Hospital for Special Surgery
- Anthony Ratcliffe, Ph.D., Synthasome, Inc.
- Robert Sah, M.D., Sc.D., University of California at San Diego
- Linda J. Sandell, Ph.D., Washington University
- Lynn Snyder-Mackler, PT, Sc.D., University of Delaware
- Tim Bhattacharyya, M.D.
- Robert H. Carter, M.D.
- Jonelle K. Drugan, Ph.D., M.P.H.
- Stephen I. Katz, M.D., Ph.D.
- Gayle Lester, Ph.D.
- Joan A. McGowan, Ph.D.
- Laura K. Moen, Ph.D.
- James S. Panagis, M.D., M.P.H.
- Bernadette Tyree, Ph.D.
- James Witter, M.D., Ph.D.
- Xibin Wang, Ph.D.