Osteoarthritis (OA) is characterized by metabolic, biochemical, and structural changes in the articular cartilage and surrounding tissues that lead to structural failure and ulceration of the load-bearing articular surface. 11 A significant capacity for matrix biosynthesis persists in OA cartilage, and the equilibrium between anabolic and catabolic processes in the joint is sufficient to make OA a slowly progressive disease in most patients. A number of possible disease-modifying osteoarthritis drugs (DMOADs) 9,38 have been identified, which in animal models prevent the development of OA or slow the progression of OA in joints in which the disease is already established. This has raised hope that such agents may be effective in humans. The need to evaluate such compounds in clinical trials has prompted substantial effort to develop outcome measures that accurately evaluate the progression of joint damage and can measure the effects of potential DMOADs. The pathologic changes in the osteoarthritic joint that can be detected with conventional radiography, with and without fluoroscopically assisted positioning of the joint 53 ; arthroscopy 2 ; ultrasonography 59 ; and magnetic resonance imaging 65 are evidence of relatively advanced disease, and are reflected by osteophytosis at the joint margins, gross changes in cartilage thickness, or ulceration of the articular surface. Even in patients with classic radiographic findings of knee OA these techniques provide only insensitive measures of disease progression. Accordingly large, carefully selected patient populations and lengthy studies will be required to evaluate the therapeutic efficacy of DMOADs. At present, none of these methodologies has been validated, or been proven suitable for monitoring the progression of OA in clinical trials in humans. This problem has provoked substantial interest in the identification and validation of a surrogate biochemical or immunochemical “marker” of OA, the level of which in body fluids may be closely linked to the progression of the disease. The serum concentration of cartilage-derived molecules (e.g., keratan sulfate [KS]) was initially believed to reflect the magnitude of articular cartilage breakdown in OA, 92 but in subsequent studies the correlation between serum concentrations of KS and the activity or severity of OA has been disappointing. 13,44,66,69 Increased levels of serum hyaluronic acid (HA) have been reported in OA, but the synovium, rather than cartilage, is the principal source of this molecule. 77 One study has shown a correlation between serum concentrations of cartilage oligomeric protein (COMP) and scintigraphic evidence of knee OA. 67 However, some have considered that it is unlikely that the serum concentration of any cartilage-derived molecule will be useful in monitoring clinically significant changes in an index joint, such as a painful knee, 8,89 because the joints contain only a small fraction of all the cartilage in the body and OA (albeit, perhaps asymptomatic), which may contribute to the serum concentration of a putative marker, will often be present in many joints other than the painful index joint. In a recent review, 64 the author noted that the serum concentration of bone sialoprotein, HA, C-propeptide of type II collagen and TGF-β-1 failed to distinguish between normal subjects and those with OA, and measurements of serum KS, COMP, aggrecan, and tumor necrosis factor (TNF) provided some discriminate power. Given the serious limitations in relating the serum concentration of an articular cartilage marker to the events in a given joint, it has been hoped that measurements made on synovial fluid from the index joint would circumvent this problem. Many of the studies cited in recent reviews of this subject have focused on the characterization and measurement of “cartilage-specific” molecules in synovial fluid. 17,44,64,92 Some so-called “disease-specific” molecules or neoepitopes, such as the Type II collagen epitope, COL2-3/4C short, and the chondroitin sulfate neoepitope, 3B3, are expressed at substantially higher levels in OA cartilage than in normal adult articular cartilage, 5,33,91 but no truly OA-specific molecule has yet been identified. It has often been assumed that a quantitative relationship exists in OA between the severity of joint damage and the concentration of some marker molecule(s) in serum or synovial fluid, 66,69,92 and that serial measurements of the marker can serve as a valid indicator of the status of the affected joint tissues (e.g., articular cartilage).