The goal is to attain an understanding of how tetracyclines inhibit collagenase production by synovial fibroblasts and influence experimental models of arthritis. The rationale for this project is based on the increasing evidence that oral administration of nontoxic doses of tetracycline compounds suppresses collagenase production by gingival fibroblasts, neutrophil chemotaxis, and delayed-type hypersentivity responses in either rodents or humans. The rabbit synovial fibroblast system will be used to test further whether tetracyclines inhibit release of collagenase activity and prostaglandin E2 synthesis in vitro. Separate experiments will assess in vivo the potential antirheumatic properties of tetracycline by analyzing whether these compounds exhibit antiinflammatory, immunosuppressive and/or collagenase-inhibition effects in the collagen and adjuvant models of inflammatory polyarthritis in rats. A final series of experiments will use a polyclonal antibody and hybridization of collagenase mRNA with a cDNA clone for synovial cell collagenase to ascertain whether the mechanism of inhibition of collagenase activity by tetracyclines involves interference with activation of latent collagenase, chelation of cations, or de novo induction of an inhibitory substance utilizing both rabbit and human synovial fibroblast cultures. The data obtained from these experimental systems have the potential to provide further evidence of whether a pilot feasibility study of the effects of oral tetracycline therapy on rheumatoid arthritis is warranted.
| Fukai, Naomi; Eklund, Lauri; Marneros, Alexander G et al. (2002) Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 21:1535-44 |
| Sewell, K L; Breedveld, F; Furrie, E et al. (1996) The effect of minocycline in rat models of inflammatory arthritis: correlation of arthritis suppression with enhanced T cell calcium flux. Cell Immunol 167:195-204 |
