Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage.
Cartilage specimens from tibial plateaus, obtained from 13 osteoarthritic (OA) patients and seven controls, were selected from three regions: zone A, center of fibrillated area; zone B, area adjacent to fibrillation, and zone C, remote region of plateau. Acid and neutral metalloproteinases and tissue inhibitor of metalloproteinase (TIMP) were extracted with 2 M guanidine. Methods were developed to selectively destroy either proteinases or TIMP to prevent cross-reaction during assay. Acid and neutral proteinases were elevated approximately 150% in OA; TIMP was elevated approximately 50%. A positive correlation (r = 0.50) was found between acid and neutral proteinase activities in OA, but not in controls. Both proteinases were elevated two-to threefold in zones A, B, and C. However, the self-active form of the acid metalloproteinase was elevated only in zones A and B (200%); it correlated well with the Mankin scores, whereas the total activities did not. TIMP was elevated (50%) only in zones A and B. Both the proteinase levels and the Mankin score were elevated to a greater extent in the medial, than in the lateral, compartment. Titration of TIMP against the two metalloproteinases indicates that there is a small excess of inhibitor over enzymes in normal cartilage. In OA, TIMP does not increase to the same extent as the proteinases; the resultant excess of proteinases over TIMP may contribute to cartilage breakdown.
Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Florida 33101.
D D
DD
Dean
J
J
Martel-Pelletier
J P
JP
Pelletier
D S
DS
Howell
J F
JF
Woessner
D000328:Adult; D000368:Aged; D002356:Cartilage / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000302:isolation & purification; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology* / Q000209:etiology; D019714:Tissue Inhibitor of Metalloproteinases
D004791:Enzyme Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D008666:Metalloendopeptidases