Identification of important interactions between subchondral bone ...

CHAPTER 2: Introduction
2.3.4 Diagnostics - biochemical markers as a tool
Several methods may be used to detect OA. X-ray detection is the golden standard method, where
narrowing of the joint space indicates cartilage loss. Other ways to detect cartilage damage include
arthroscopy and magnetic resonance imaging (MRI) 54,119 . However, OA is often diagnosed at late
stages when the pain is unbearable for the patients, and the damages are too severe to repair.
Today, many biochemical markers have been developed for the purpose of diagnosing the stage or
degree of a specific disease.
A biochemical marker is a single molecule or fragment of a molecule that is released
into biological fluids (e.g. blood and urine) during tissue pathogenesis 54 . An increase in a specific
biochemical marker indicates alterations of turnover, i.e., increased synthesis or breakdown 120 .
Biochemical markers give a more accurate diagnosis of the severity of a disease for each patient, so
that treatment could be designed specifically for the individual patient. Furthermore, the response
to treatment or slow-down of the disease-progression can also be detected with these biochemical
markers.
OA is a disease affecting the whole joint and potential biochemical markers could
originate from cartilage, bone, synovium, ligaments, tendons and muscles. However, the systemic
levels from muscles, and some of the other tissues may exceed the small alterations seen from the
OA-joint. At present, clinical studies indicate that different biochemical markers of cartilaginous
matrix proteins may be useful to predict the early stages of cartilage damage and progression in
OA. However, detection of OA by biochemical markers alone is not possible yet, as they measure
systemic levels 54 . Nevertheless, the market for developing biochemical markers is increasing as it is
possible to design more target-specific biochemical markers (e.g. neo-epitopes with post-
translational modifications) or combine a specific selection of markers that represent one unique
disease 121,122 .
In OA, a central hallmark is the gradual destruction of articular cartilage and
alterations in the subchondral bone 121 . The turnover of subchondral bone increases in early OA,
which can be measured by increased formation and degradation of collagen type I (fig. 10A) and
osteocalcin 123,124 . The resorption of collagen type I by osteoclasts is mediated by the protease,
cathepsin K, which generates the neo-epitope, C-terminal telopeptide of collagen type I
(CTX-I) 125,126,127 . However, studies have shown that both CTX-I and osteocalcin decrease in the
body fluids of OA patients, indicating that overall bone turnover decreases in OA, whereas the
increased turnover seen in subchondral bone is lost in systemic levels 128,129 .
The turnover of cartilage is normally maintained by a balance between catabolic and
anabolic processes; however, in the case of pathological matrix destruction, the rate of cartilage
degradation exceeds the rate of formation, resulting in a net loss of cartilage matrix. During
degradation of articular cartilage, MMPs and aggrecanases are considered the most important
proteases for degradation of articular cartilage 130,131,132 . The key target proteins in cartilage is
collagen type II and aggrecan (fig. 10B+C). Other important molecules in articular cartilage
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