In studies of alterations in matrix constituents in disease we have particularly focused on rheumatoid arthritis and osteoarthritis. We use, as indicators of ongoing processes in the tissue, altered matrix protein synthesis and accumulation or loss of a particular protein. An additional indicator is fragment formation in early events in the cartilage, long before clinical signs of cartilage involvement become apparent. We have thus shown that in joints with single site lesions of fibrillation, molecular alterations are of similar nature as in late stage osteoarthritis cartilage indicating that these lesions represent an early event in the process. Particularly, COMP, fibronectin, CILP and asporin are markedly upregulated in synthesis and abundance in the tissue, although in a different distribution compared to normal age and site matched tissue. At the protein level a number of matrix constituents show significant alterations in the tissue.
An essential observation is that the whole articular cartilage is involved in disease, since joints with single superficial lesions show alterations at the molecular level also at sites with cartilage appearing normal.
In models of articular cartilage involvement in disease, degradation of tissue structural elements is induced by inflammatory cytokines, particularly IL-1. In a distinct sequence of degradative events, aggrecan is first fragmented, followed by COMP, fibromodulin and lost collagen. By the identification of specific fragmentation sites in e.g. fibromodulin, it has been possible to develop specific assays, that can be used to identify the enzyme active has MMP-13. This enzyme only appears in the tissue at the time of fibromodulin cleavage. Interestingly increased levels of COMP/COMP-fragments in serum of patients can be used to reveal active processes in the articular cartilage and shows correlations to subsequent (years later) joint destruction observable by X-ray, both in rheumatoid arthritis and osteoarthritis. This molecular marker technology provides openings for early detection of tissue damage, well before the time when the process has resulted in damage that can be detected by imaging techniques. Analysis of BSP levels shows early bone involvement.
Early osteoarthritic cartilage
Rheumatoid synovium
Studies of patients with rheumatoid arthritis at the very early stages in disease before clinical signs of cartilage damage, show that serum levels of COMP/COMP-fragments are much elevated in cases with aggressive disease showing extensive tissue damage within a few years time. In patients with no or little joint damage over the same period COMP levels are close to normal. Other markers of altered cartilage metabolism include aggrecan fragments in the synovial fluid. However, such fragments, probably primarily those containing glycosaminoglycan chains, appear not to generally reach the general circulation, precluding their use as serum markers of processes in the articular cartilage. Patients with rheumatoid arthritis show increased synovial fluid levels of fragments also of the bone protein BSP, indicating involvement of the underlying bone. Also the levels of BSP in serum are elevated as the levels of osteocalcin, indicative of the altered bone metabolism often leading to osteoporosis.