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

Chockalingam, P. S. ; Sun, W. ; Rivera-Bermudez, M. A. ; Zeng, W. ; Dufield, D. R. ; Larsson, Staffan LU orcid ; Lohmander, Stefan LU orcid ; Flannery, C. R. ; Glasson, S. S. and Georgiadis, K. E. , et al. (2011) In Osteoarthritis and Cartilage 19(3). p.315-323
Abstract
Objective: 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... (More)
Objective: 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. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aggrecan, Aggrecanase, Joint injury, Synovial fluid, Osteoarthritis
in
Osteoarthritis and Cartilage
volume
19
issue
3
pages
315 - 323
publisher
Elsevier
external identifiers
  • wos:000288527300010
  • scopus:79951857290
  • pmid:21163358
ISSN
1063-4584
DOI
10.1016/j.joca.2010.12.004
language
English
LU publication?
yes
id
dedc7fc9-f9c8-4423-a7a0-ace3dca722c7 (old id 1936151)
date added to LUP
2016-04-01 10:59:45
date last changed
2024-01-07 06:11:00
@article{dedc7fc9-f9c8-4423-a7a0-ace3dca722c7,
  abstract     = {{Objective: 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. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.}},
  author       = {{Chockalingam, P. S. and Sun, W. and Rivera-Bermudez, M. A. and Zeng, W. and Dufield, D. R. and Larsson, Staffan and Lohmander, Stefan and Flannery, C. R. and Glasson, S. S. and Georgiadis, K. E. and Morris, E. A.}},
  issn         = {{1063-4584}},
  keywords     = {{Aggrecan; Aggrecanase; Joint injury; Synovial fluid; Osteoarthritis}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{315--323}},
  publisher    = {{Elsevier}},
  series       = {{Osteoarthritis and Cartilage}},
  title        = {{Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor}},
  url          = {{http://dx.doi.org/10.1016/j.joca.2010.12.004}},
  doi          = {{10.1016/j.joca.2010.12.004}},
  volume       = {{19}},
  year         = {{2011}},
}