CHECKing biochemical markers in early-stage knee and hip osteoarthritis, a critical appraisal

Abstract

Osteoarthritis (OA) is the most common joint disease and poses a large social and financial burden for societies worldwide. OA is characterized by symptoms of pain, stiffness, and incidental soft tissue swelling of synovial joints. Synovial joints, such as knees and hips, unite bone ends covered by thin layers of articular cartilage in a joint capsule with synovial tissue on its inner surface. Structural signs of OA include articular cartilage loss, growth of bone spurs along the joint margins (osteophytes), and inflammation of synovial tissue (synovitis). These structural signs follow or precede changes in matrix turnover (i.e. degradation and synthesis) of cartilage, bone, and/or synovial tissue and, presumably, are reflected in an altered release of matrix molecules (e.g. synthesis and degradation products of the matrices). In this thesis serum and urinary levels of such molecules were related to radiographic signs and pain of early-stage knee and hip OA in subjects of CHECK (Cohort Hip and Cohort Knee). CHECK is a nationwide cohort that is unique worldwide and is initiated and funded by the Dutch Arthritis Association. Using biochemical markers, especially cartilage degradation and synovitis could be identified as processes underlying the development of radiographic signs and early-stage knee and hip OA. Interestingly, degradation of collagen fibrils in articular cartilage especially appeared to be a risk factor for progression of radiographic knee OA when collagen synthesis was low (i.e. dissociation of degradation and synthesis). Also bone turnover (and with that maybe bone mineral density) could be a relevant factor in the development of radiographic OA, but its effect may be different between knee and hip. Among the metabolic processes monitored, synovitis and osteophyte development appeared important in causing joint pain in knee OA. Finally, also products of adipose tissue, so-called adipokines, could play a role in the pathogenesis of knee OA. Among them, especially leptin could act as a mediator in the effects of obesity (more fat) and female gender (other fat distribution) on knee OA. Notably, the putative cartilage (collagen type II) degradation marker, CTX-II, showed striking similarities with markers of bone metabolism and associations with bone density distant from joints. These data question cartilage specificity of this marker and suggest that CTX-II may also originate from bone. Furthermore, the marker COMP (cartilage oligomeric matrix protein) that is most frequently interpreted as a marker of cartilage degradation might in early-stage OA mainly originate from (inflamed) synovial tissue instead. Although the associations between marker levels and radiographic knee and hip OA were very informative on the pathogenic mechanism behind early-stage OA, they were too weak to be of direct use for clinical research and practice. Further research is needed for increasing the specificity of markers for joints and/or joint compartments, decreasing interference from systemic distribution and metabolism of markers, and better understanding of the pathogenesis of OA. This way, we may succeed in developing markers for detecting critical events in the pathogenesis of OA in relevant OA (sub)populations.