Cysteine Proteinase Inhibitors Decrease Articular Cartilage and Bone Destruction in Chronic Inflammatory Arthritis

Wiley - Tập 37 Số 2 - Trang 236-247 - 1994
Ronald E. Esser1,2,3,4, Richard A. Angelo1,2,3,4, Mark D. Murphey1,2,3,4, Lynnetta M. Watts1,2,3,4, Larry P. Thornburg1,2,3,4, James T. Palmer1,2,3,4, Jamil W. Talhouk5, Robert E. Smith5
1Immunology Research, Marion Merrell Dow Research Institute, Kansas City, Missouri
2Prototek Inc., Dublin, California.
3the Department of Diagnostic Radiology, University of Kansas Medical Center, Kansas City, Kansas
4the Department of Pathology, University of Missouri School of Veterinary Medicine, Columbia, Missouri
5University of Missouri, Columbia, United States

Tóm tắt

AbstractObjective. To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis.Methods. The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type II collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods.Results. All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity. Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition, fluoroketone treatment significantly reduced the severity of clinical joint disease and decreased the destruction of articular cartilage and bone. Quantitative analysis of radiographic images indicated that treatment significantly reduced soft tissue changes, periosteal proliferation, and bone erosion, but only partially reduced juxtaarticular osteoporosis.Conclusion. These studies suggest that cysteine proteinase inhibitors may limit tissue destruction in diseases such as rheumatoid arthritis.

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Wiley

Tập 37 Số 2

236-247

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