Arthritis Research

Detecting the Warning Signs of Arthritis

Target Condition: Osteoarthritis

Traditional Approach: Medication, Steroid injections, walking aids, surgery

New Approach: Early Diagnosis by monitoring biological markers

Progress: Specific target molecule has been identified that can aid in diagnosis and prevention.

    

Investigator Dr. Chuan-ju Liu

Over 40 million Americans have been diagnosed with osteoarthritis, a condition second only to cardiovascular disease as a cause of disability in Americans over 50 years of age. Nonsurgical treatments, even when they provide temporary relief of symptoms, do not address the underlying disease processes. Ultimately many sufferers will require surgical intervention, such as joint replacement surgery, to achieve meaningful improvement, as reflected by the fact that more than 120,000 artificial hip joints are implanted in the United States annually.

Despite the prevalence of the condition, little is known about how osteoarthritis develops or how it progresses. Many arthritis sufferers are not seen by a doctor until long after they have experienced substantial loss of cartilage and impairment of function. When detection of cartilage degeneration is made so late in the disease process, the body’s natural resources are are no longer effective in stopping or reversing joint degeneration.

Studies in this area have identified a “target” molecule, cartilage oligomeric matrix protein (COMP), which is found in abundance in the extracellular matrix of joint tissues. The significance of COMP derives from the fact that its degradation appears to herald the onset of arthritis.

COMP molecules: A purified sample of cartilage oligomeric matrix protein (COMP), a key constituent of cartilage, as seen under an electron microscope. The molecular structure of proteins often gives clues to their function; in the case of COMP, its characteristic five-pointed “bouquet” structure (indicated by arrows) marks it as an important interactive molecule. (Original magnification: 500,000x)


Early studies in this area resulted in purifying COMP from human articular cartilage and delineating its structure and tissue distribution in normal and diseased cartilage. Specific mono- and polycolonal antibodies against COMP have been produced in our laboratories. These reagents have been used to determine the tissue distribution of COMP by immunostaining, the amounts and types of COMP in biological fluids using competitive enzyme-linked immunosorbent assay (ELISA) and western blot analysis.

The key finding in these studies is that the tissue distribution for COMP becomes altered in arthritic states. Analysis of synovial fluid revealed increased amounts of degradation fragments of COMP as well as specific degradation fragments that serve as “flags” for altered cartilage metabolism.

Visualizing cartilage: Surface cross section of cartilage. The tissues have been subjected to immunostaining in order to highlight COMP, which selectively takes up the red stain. Normal cartilage is shown on the left, cartilage from a patient with rheumatoid arthritis in the center, and cartilage from a patient with osteoarthritis on the right. Of particular interest to us is the density of the chondrocyte population, surface fibrillation (raggedness), and altered distributions of COMP.

Two clinical studies were subsequently conducted to test the utility of COMP as a biological marker of arthritis. The first demonstrated greater levels of COMP in patients with osteoarthritis, rheumatoid arthritis, and other arthritides than in healthy “controls” subjects. The second study focused on a potential prearthritic condition that arises inpatients with traumatic bone bruises that have been detected detected by magnetic resonance imaging (MRI). This study revealed that there is about 10 times higher synovial fluid COMP levels in the injured knees of these patients than in their noninjured knees.

Encouraged by these findings, we have planned future studies to determine the specific enzymes that degrade COMP, to develop more specific reagents toward degradative fragments (neoepitopes), and to conduct longitudinal tracking of COMP synovial levels in patients who exhibit prearthritic symptoms.