Orthopaedic surgeon Reuben Gobezie, MD, two-time Orthopaedic Research and Education Foundation (OREF) grant recipient, knows arthritis is the most common disorder in musculoskeletal medicine. “Not a day goes by in my office that I don’t see somebody with arthritis,” he said.
“Unfortunately, we don’t understand how it happens. We don’t have a single therapeutic agent that can address the mechanism of the disorder,” stated Dr. Gobezie, chief of shoulder and elbow surgery at University Hospitals of Cleveland and former head of the Musculoskeletal Proteomics Center at Case Western Reserve University.
Courtesy of University Hospitals
Proteomics at the forefront
“Our first study compared the knee joint fluid of healthy patients with that of patients with arthritis,” said Dr. Gobezie. Using mass-spectrometer–based proteomics, the goal was to identify new biomarkers specific to OA and rheumatoid arthritis, as well as possible target proteins that could be used to develop new pharmacologic therapeutics. One of the more promising proteins identified was phospholipase A2 (sPLA2-IIA), which showed substantial elevations in both early and late OA synovial fluid.
“We also found that, contrary to what many people believe about arthritis being a cartilage-based disease, the synovial tissue seems to be influencing the progression of this disorder at least as much as, if not more than, the cartilage,” explained Dr. Gobezie.
Dr. Gobezie is using his second OREF grant to validate his findings in a controlled environment.
The current project emerged from a collaboration between Dr. Gobezie and rheumatologist David M. Lee, MD, associate professor in medicine, Harvard Medical School. Again using mass spectrometry, this study is exploring the in vivo role of sPLA2-IIA in the pathogenesis of OA using destabilization of the medial meniscus (DMM) in a mouse model. DMM leads to cartilage damage (proteoglycan depletion, fibrillation, and erosions) in weight-bearing sections of the joint within 4 to 8 weeks, with progressive damage noted through 26 weeks.
“Our rationale for these experiments is several-fold,” indicated Dr. Gobezie. “We observed a strong sPLA2-IIA upregulation in human patients with meniscal damage and early cartilage changes of OA. We chose the DMM model because it may provide insight into postmeniscal damage pathophsyiology in early OA. Additonally, human sPLA2-IIA transgenic mice allow us to closely model the activity of this human sPLA2 isoform.”
As with all nonclinical studies, the DMM methodology does not fully replicate arthritis as it is seen in humans. For example, subchondral sclerosis evident in humans with later stage arthritis does not occur. Nevertheless, when applied appropriately, the DMM model produces findings that may be useful in understanding the pathophysiology of OA.
sPLA2-IIA in the model
The experiment starts with researchers cutting the ligament that holds the meniscus in place within the knee, which results in a progression of arthritis that goes from healthy knee all the way through late arthritis within 30 days.
“We then take different time points along that spectrum from healthy as time zero to 30 days. We homogenize those joints, then sequence the proteins within them,” said Dr. Gozebie, who expects to see a strong correlation between sPLA2-IIA and the progression of arthritis.
Based on results to date, the team hypothesizes that arthritis is the result of a chronic wound signal that starts in the meniscus. When the chronic wound doesn’t heal, it spreads to the synovial tissue and drives a clinical wound pattern that eventually deteriorates and erodes the joint. Importantly, there are strong indications that a therapeutic intervention based on sPLA2-IIA may stop the progression of arthritis.
In addition to achieving promising results in the lab, the team is encouraged that their work is gaining significant attention through publication in major orthopaedic and basic science journals.
Still, Dr. Gobezie is deeply concerned that financial pressures might slow or halt their research. “Clinician scientists are becoming an endangered species. The scarcity of funding threatens our work and is driving away new scientists,” he explained. “Until funding levels for the National Institutes of Health are increased substantially—or additional large-scale funding sources are developed—all our work is at risk.”
From a patient perspective, Dr. Gobezie explained that arthritis strikes at the heart of what most Americans value highly—activity and motion. “Our work represents a significant contribution toward developing novel therapeutics that can prevent the progression of arthritis and relieve the pain many of our patients struggle with every day,” said Dr. Gobezie. “The ultimate objective is to eliminate arthritis altogether and put ourselves out of business.”
Mark Crawford is a contributing writer for OREF and can be reached at firstname.lastname@example.org
- United States Bone and Joint Initiative: The Burden of Musculoskeletal Diseases in the United States, Second Edition. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2011.