The long-term objectives of this proposal are to define the biochemical mechanisms underlying continued cartilage degradation in staphylococcal septic arthritis and to develop therapeutic regimens to prevent post-infectious inflammatory cartilage destruction. The experimental rationale is based on our results showing that staphylococcal joint infection results in the rapid onset of cartilage degradation and in persistent cartilage destruction in spite of early antibiotic treatment. Addition of an anti-inflammatory agent with antibiotic therapy decreases but does not override the processes of cartilage degradation. The results of these studies are applicable to rheumatology, orthopaedics and infectious diseases. The hypothesis to be tested is that reduction of inflammatory post-infectious cartilage degradation is analogous to treatment of cancer in which a combination of therapeutic modalities are required to achieve successful results. The multifactorial approach includes synovial lavage to decrease the levels of debris and inflammatory exudate. The efficacy of wash techniques will be expanded by application of systemic and intra-articular agents to block cartilage degradation and synovial inflammation.
The Specific Aims are to: (1) Characterize the Staphylococcal-induced cartilage degradation following antibiotic and NSAID therapy in conjunction with lavage at 2, 4 and 7 days after infection. Analysis of the cartilage will be carried out (la) at 10 days post-infection to establish short-term proteoglycan losses and (lb) at three weeks, seven weeks and three months post-infection to determine long-term events; (2) Extend the combination treatment by analyzing the effects of adding two different proteinase inhibitors in the lavage solution, one an analog of tissue inhibitor of metalloproteinase (TIMP-like) and the other, alpha 2-macroglobulin; (3) Extend the combination treatment by adding transforming growth factor beta to enhance cartilage repair and by adding antibodies to purified staphylococcal cartilage degrading factor (Staph Factor) in vitro and in vivo; (4) Expand wash techniques and induce reparative properties to the cartilage and synovium by adding insulin, epidermal growth factor and insulin-like growth factor I to (4a) cartilage explant cultures challenged with Staph Factor and (4b) in the infected joint in a lavage solution at a stage after bacteria are killed and inflammation has subsided. Experiments will use in vitro and in vivo models of Staphylococcal infectious arthritis. Effects of antibiotic and anti-inflammatory therapies coupled with (a) proteinase inhibitors and (b) growth factors will be assessed by quantitation of cartilage proteoglycan synthesis and degradation.
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| Mohtai, M; Smith, R L; Schurman, D J et al. (1993) Expression of 92-kD type IV collagenase/gelatinase (gelatinase B) in osteoarthritic cartilage and its induction in normal human articular cartilage by interleukin 1. J Clin Invest 92:179-85 |
| Lane, N E; Williams 3rd, R J; Schurman, D J et al. (1992) Inhibition of interleukin 1 induced chondrocyte protease activity by a corticosteroid and a nonsteroidal antiinflammatory drug. J Rheumatol 19:135-9 |
| Williams 3rd, R J; Smith, R L; Schurman, D J (1991) Purified staphylococcal culture medium stimulates neutral metalloprotease secretion from human articular cartilage. J Orthop Res 9:258-65 |
| Williams 3rd, R J; Smith, R L; Schurman, D J (1990) Septic arthritis. Staphylococcal induction of chondrocyte proteolytic activity. Arthritis Rheum 33:533-41 |
