In vivo effects of stromelysin on the composition and physical properties of rabbit articular cartilage in the presence and absence of a synthetic inhibitor.
OBJECTIVE
To characterize the effects of intraarticular injection of recombinant human stromelysin (SLN) on the matrix composition and physical properties of cartilage from lapine stifle joints and the modulation of these effects by the systemic administration of an N-carboxyalkyl synthetic matrix metalloproteinase inhibitor, L-696,418.


METHODS
Female 6-8-week-old New Zealand white rabbits received an intraarticular injection of 100 micrograms activated SLN in 1 stifle joint and buffer in the contralateral control knee; these animals were killed after 1 hour. A separate group of animals received an intravenous injection of either 30 mg/kg L-696,418 or buffer prior to intraarticular injection of SLN. Joints were dissected and analyzed for proteoglycan (PG) loss into joint fluid, tissue biochemical composition, and histology by toluidine blue or anti-VDIPEN antibody staining, or were frozen for physical property analysis. Disks of femoropatellar groove cartilage were harvested from the stifle joint and tested in uniaxially confined compression for determination of electromechanical and mechanical properties.


RESULTS
Lapine stifle joints that received injection of SLN without systemic administration of L-696,418 showed a 13-fold increase in loss of PG into synovial fluid. Cartilage from these joints showed significant decreases in streaming potential at 1 Hz and electrokinetic coupling coefficient, but no change in equilibrium modulus, dynamic stiffness, or hydraulic permeability. Systemic treatment with L-696,418 resulted in a significant decrease in loss of PG into joint fluid and elimination of changes in cartilage high-frequency streaming potential and coupling coefficient in joints that were injected with SLN.


CONCLUSIONS
The 1-hour exposure to SLN in vivo resulted in loss of PG and exposure of the VDIPEN epitope of the aggrecan core protein in the superficial region of the tissue near the articular surface. This highly localized degradation resulted in electromechanical behavior changes, but little or no change occurred in mechanical properties. Systemic administration of L-696,418 significantly decreased loss of PG from cartilage and prevented the highly localized tissue degradation and the resultant changes in electromechanical behavior caused by intraarticular SLN injection.
D000818:Animals; D001696:Biomechanical Phenomena; D002358:Cartilage, Articular / Q000033:anatomy & histology / Q000187:drug effects*; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits
D004151:Dipeptides; D011480:Protease Inhibitors; C085083:N-(1-carboxyethyl)-alpha-(2-phenylethyl)glycyl-leucine, N-phenylamide; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3