In vivo assessment of degenerative biological changes to cartilage can be evaluated by assays of enzymes, enzymeinhibitors, and protein fragments, generically termed biological markers or biomarkers. Biomarkers have the potential to become indicators of normal biological processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.
The in vivo physical and biological environment must be considered together when evaluating biomar-kers (see Figure 77.1). Cartilage oligomeric matrix protein (COMP), a prominent constituent of articular cartilage, is up-regulated following cyclical compression in situ and may play an important role in transducing mechanical forces in the extracellular matrix to the cell (Wong et al, 1999). For example, competing marathon runners whose joints are exposed to repetitive loading during frequent running training and competition have elevated serum COMP concentrations compared to healthy control subjects (Neidhart et al., 2000). In another study (Miindermann et al., 2005; Mundermann et al., 2004), reduced COMP levels were associated with the adduction moment at the knee, suggesting that mechanical variations in the way individuals perform the same activity are related to the differences in the cartilage COMP levels. In contrast, keratan sulfate, a biomarker reflecting the rate of cartilage catabolism (Thonar et al., 1985), did not significantly change in 15 marathon runners before, immediately after, and 48 hours after the completion of a training marathon (Sweet et al., 1992). Thus, these data suggest that with careful and regular training, running a marathon appears not to increase the rate of degradation of articular cartilage. Changes in COMP and keratan sulfate concentrations suggest that although exercise may not lead to an acute degenerative response of major cartilage constituents including chondrocytes, proteoglycans, and collagen, other constituents such as COMP may be adversely affected.
In osteoarthritic cartilage, the sensitive equilibrium between tissue degeneration and synthesis is disrupted and degenerative processes preponderate. Fragments of proteoglycans or proteins (glucosaminoglycan and COMP) and catabolic and other enzymes, as well as their inhibitors (metalloproteinases, interleukin-1, interleukin-1 receptor antagonist) found in body fluids, may reflect net cartilage degeneration or increased metabolic activity (Otterness et al., 2001).
Quantifying blood serum concentrations of bio-markers is a promising yet minimally invasive tool to investigate the tissue's response to mechanical load in vivo. To date, very little is known about changes in biomarker concentrations that occur in relation to loads placed upon the joint during everyday activities (Miindermann et al., 2005; Miindermann et al., 2004). Similar physical activities may promote tissue synthesis in the healthy joint while accelerating degenerative processes in the osteoarthritic joint.
There are still substantial gaps in our ability to interpret the relationships between changes in biomar-kers and the loading environment of cartilage. Specificity of the marker to cartilage and the joint of interest always remains a question in studies where markers are extracted from serum. In addition, controlling for the influence of chronic versus transient loads also is an important consideration. Thus, there is a need for further research in this area to define and identify the role of biomarkers in the evaluation of knee osteoarthritis.
Joint Structure, Osteoarthritis, and Aging
The normal function of diarthrodial joints such as the knee involves providing a wide range of mobility while sustaining large forces that are multiples of the body's weight. For example, normal function of the knee during stair climbing requires the knee to flex in the range between 0 and 90 degrees while sustaining com-pressive forces on the articular surface that can exceed four times body weight. As previously discussed, the biology of cartilage is influenced by the mechanical environment of the joint. Thus, the intrinsic mechanical environment (force and motion) is an important consideration in the context of understanding the factors that influence the initiation and progression of osteo-arthritis. The intrinsic forces and motions at the joint are dependent on complex interactions between the shape of the articulating surfaces, passive soft tissue properties surrounding the joints, and active muscle contraction. Thus, individual anatomical variations in joint anatomy that influence joint movement or the forces on the joint can influence the mechanobiology of the articular cartilage and ultimately play a role in the factors associated with the progression of osteoarthritis. For example, the association of joint laxity with osteo-arthritis at the knee will be discussed in the next sections of this chapter.
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