Osteoarthritis (OA) and disuse atrophy are both important pathological processes of articular cartilage, but are distinct because the events in OA ultimately progress to failure of the cartilage matrix, and cartilage in disuse atrophy can successfully repair. The applicant's governing hypothesis is that there are fundamental differences in the metabolism of aggrecan and link protein in articular cartilage of joints with OA and disuse atrophy, and an understanding of these will indicate those events that may be crucial in cartilage degeneration. Results of previous studies using canine experimental models of OA and disuse atrophy have shown that there are differences in metabolism of aggrecan and link protein. New molecular technologies now allow studies to be made to describe precise metabolic changes of aggrecan and link protein through the depth of the cartilage during the early development of these pathologies. The studies are designed to provide important new understanding of the molecular mechanisms ongoing in OA and disuse atrophy. Hypothesis 1: The proteoglycan cleavage products of aggrecan in the synovial fluids of OA, disuse and control joints are similar; the proteolytic cleavage products of link protein in disuse atrophy and control joints are similar, but in OA the link protein degradation products are different. Hypothesis 2: In OA and disuse there are changes in the rates of gene expression and synthesis of aggrecan and link protein; in OA there is an altered ratio of the rates of synthesis of aggrecan and link protein, whereas in disuse any changes in the rates of synthesis of aggrecan and link protein will occur in a balanced manner. Hypothesis 3: In OA cartilage, but not disuse cartilage, there will be a development of a change in the content and ratio of link protein and aggrecan of OA cartilage, whereas in the disuse cartilage, the normal ratio will be maintained. Hypothesis 4: The appearance of native 3B3 epitope will occur coincidental with a change of the ratio of aggrecan and link protein being synthesized, and is the earliest identifiable indicator of OA cartilage processes. Established canine experimental models of OA and disuse atrophy will be studied during the early development of their pathologies using an interdisciplinary approach (molecular biology, immunochemistry, and compositional analysis). The applicants will quantitate; (1) specific N-terminal sequences of proteolytic fragments of aggrecan and link protein in synovial fluids; (2) the change in the gene expression and synthesis of aggrecan and link protein by chondrocytes through the depth of the articular cartilage; (3) the changes in the levels of aggrecan and link protein through the depth of the articular cartilage; (4) the levels of native 3B3 epitope through the depth of the articular cartilage and in the synovial fluid.
| Valhmu, W B; Stazzone, E J; Bachrach, N M et al. (1998) Load-controlled compression of articular cartilage induces a transient stimulation of aggrecan gene expression. Arch Biochem Biophys 353:29-36 |
| Valhmu, W B; Palmer, G D; Dobson, J et al. (1998) Regulatory activities of the 5'- and 3'-untranslated regions and promoter of the human aggrecan gene. J Biol Chem 273:6196-202 |
