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Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor.

AbstractOBJECTIVE:
To evaluate aggrecanase activity after traumatic knee injury in a rat model by measuring the level of aggrecanase-generated Ala-Arg-Gly-aggrecan (ARG-aggrecan) fragments in synovial fluid, and compare with ARG-aggrecan release into joint fluid following human knee injury. To evaluate the effect of small molecule inhibitors on induced aggrecanase activity in the rat model.
METHOD:
An enzyme-linked immunosorbent assay (ELISA) was developed to measure ARG-aggrecan levels in animal and human joint fluids. A rat model of meniscal tear (MT)-induced joint instability was used to assess ARG-aggrecan release into joint fluid and the effects of aggrecanase inhibition. Synovial fluids were also obtained from patients with acute joint injury or osteoarthritis and assayed for ARG-aggrecan.
RESULTS:
Joint fluids from human patients after knee injury showed significantly enhanced levels of ARG-aggrecan compared to uninjured reference subjects. Similarly, synovial fluid ARG-aggrecan levels increased following surgically-induced joint instability in the rat MT model, which was significantly attenuated by orally dosing the animals with AGG-523, an aggrecanase specific inhibitor.
CONCLUSIONS:
Aggrecanase-generated aggrecan fragments were rapidly released into human and rat joint fluids after injury to the knee and remained elevated over a prolonged period. Our findings in human and preclinical models strengthen the connection between aggrecanase activity in joints and knee injury and disease. The ability of a small molecule aggrecanase inhibitor to reduce the release of aggrecanase-generated aggrecan fragments into rat joints suggests that pharmacologic inhibition of aggrecanase activity in humans may be an effective treatment for slowing cartilage degradation following joint injury.
AuthorsP S Chockalingam, W Sun, M A Rivera-Bermudez, W Zeng, D R Dufield, S Larsson, L S Lohmander, C R Flannery, S S Glasson, K E Georgiadis, E A Morris
JournalOsteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 19 Issue 3 Pg. 315-23 (Mar 2011) ISSN: 1522-9653 [Electronic] England
PMID21163358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • Aggrecans
  • Biomarkers
  • Endopeptidases
  • aggrecanase
Topics
  • Aggrecans (metabolism)
  • Animals
  • Biomarkers (metabolism)
  • Disease Models, Animal
  • Endopeptidases (metabolism)
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Knee Injuries (enzymology)
  • Rats
  • Rats, Inbred Lew
  • Synovial Fluid (enzymology)

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