Molecular and clinical studies of cartilage and bone macromolecules in arthritis

Sammanfattning: The pathogenesis of inflammatory arthritides include synovial inflammation and joint tissue destruction. Tissue destruction has traditionally been regarded a consequence of inflammation, but recent observations indicate that the processes are not always closely linked and may proceed uncoupled. The ultimate target organs for the destructive process are articular cartilage and bone. This thesis focuses on the pathophysiological changes in these tissues in arthritis patients differently prone to joint damage. Proteins or fragments of proteins released into synovial fluid and blood, so called molecular markers, were studied, as indicators of ongoing processes. Groups representing destructive rheumatoid arthritis (RA), non-destructive RA and psoriatic arthritis, were studied. In RA, high serum levels of the cartilage component COMP and low levels of the 846 epitope of aggrecan, correlate to joint damage. High synovial fluid aggrecan levels correlate to cartilage destruction. The pattern in psoriatic arthritis resembles in this respect that in non-destructive RA. Most changes occur early in the disease course, indicating a critical period for long-term joint damage. The findings will be useful to prognosticate future joint damage and facilitate the selection of patients likely to benefit from tissue-protective therapy. The observations indicate involvement of different pathogenic mechanisms in destructive and non-destructive arthritis. In a project aimed at exploring the turnover of a putatively regulatory cartilage protein with molecular marker potential, chondroadherin, I have studied its release from cartilage and interactions with other cartilage matrix components. Cartilage destruction in arthritis is accomplished by matrix metalloproteases. Chondroadherin was released from cartilage when treated with APMA, known to be an activator of latent metalloproteases. The released protein appeared to be intact and associated to monomeric collagen type II, a major structural element in cartilage. The interaction between chondroadherin and collagen II was characterised by electron microscopy and surface plasmon resonance assays. Future work aims at defining the interacting sites on collagen and chondroadherin, respectively, and to study the functional consequences of chondroadherin for collagen assembly into fibrils.