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Biochemical markers for osteoarthritis: from the present to the future and back to the past.

Matrix molecules turning over in articular tissues, or their metabolic fragments, are expected to appear in the serum or urine where they can be quantified, generally by ELISA or radioimmunoassay. These assays for “markers” of joint tissue turnover provide the possibility of sensitive correlations with clinical and radiological assessment of joint damage. This possibility is intuitively attractive to the pharmaceutical industry for drug development, since alterations in the levels of biochemical markers in serum or urine may, in theory, precede slowly developing radiological and clinical change. However, it is well recognized that the measurement of joint tissue molecules or fragments in the serum or urine reflect complex metabolism in a multicompartment model, which can also be affected by the phasic nature of OA1. One approach is to use “clusters” of markers, chosen more or less for their presumed biochemical function2. In the interesting report by Patrick Garnero and collaborators3 in this issue of The Journal, 10 molecular markers of bone, cartilage, and synovium have been used and correlated with disease activity and radiological joint damage. The cohort, gathered from 26 rheumatology departments in France, consisted of 376 patients taken from a larger group of patients with hip OA that participated in a clinical trial on diacerein (ECHODIAH). The biochemical measurements were done at baseline, i.e., before the test drug was administered. Using principal component analyses, the investigators found that the different markers could be segregated into 5 different clusters, which, they speculate, may reflect different pathophysiological processes of OA, namely bone turnover, cartilage degradation, or synovitis. Among the markers analyzed, urinary CTX II demonstrated the most consistent association with both joint pain [C-reactive protein (CRP) elevation was also associated with pain] and the width of the radiological joint space. In another recent study4 it was found that knee OA, spine disc degeneration, and hand OA contributed significantly and independently to increased urinary CTX II levels in postmenopausal women. Also, an interesting association noted by Garnero, et al3 relates to serum YKL-40 (cartilage GP39). This glycoprotein was considered to be closely tied to cartilage differentiation and chondrocyte and synoviocyte proliferation, but was found to segregate together with serum CRP, suggesting that YKL-40 may also be an inflammatory marker. The authors correctly point out that because of the cross-sectional design of their study, they cannot use their data for prediction of joint damage. However, in a recent large epidemiological study it was found also that urinary CTX II was associated with both prevalence and progression of radiographic OA at the knee and hip, and the association seemed stronger in subjects with joint pain5. The correlation between CTX II and symptoms is interesting, but it would be perverse to suggest (and the authors do not) that a biochemical marker should be used to determine who has symptoms. Almost certainly, the ECHODIAH cohort is heavily biased in favor of patients with significant symptoms. But obtaining low selection bias “control” populations is a nontrivial matter, with many issues to consider. Among large epidemiological studies with low selection bias is the Canadian Multicenter Osteoporosis Study (CaMOS), whose sampling frame consists of all residential telephone numbers in predetermined geographical study centers, from which roughly 10,000 subjects have been randomly selected. Now in its seventh year, CaMOS has provided “normative” data for quality of life and stability over time6. Extending the concept of “normative” data to biochemical markers has a number of problems, including how to handle asymptomatic subjects with radiological OA. However, a population with low selection bias, studied longitudinally for a long time, would be needed to give us a clearer insight into the biological significance of biochemical markers. So, from the present state of the art, what does the future hold for biochemical markers in body fluids? If one takes the point of view that markers reflecting articular cartilage metabolism are central to the prognosis and treatment of OA, other cartilage-specific molecules, such as the cartilage specific (V+C) and hyperglycosylated forms of fibronectin7,8, need to be explored. However, in terms of