Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor
| Autor: | M.A. Rivera-Bermudez, Staffan Larsson, Weilan Zeng, Carl R. Flannery, Priya S. Chockalingam, S.S. Glasson, W. Sun, Katy E. Georgiadis, L.S. Lohmander, D.R. Dufield, Elisabeth A. Morris |
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| Rok vydání: | 2010 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Rat model Biomedical Engineering Enzyme-Linked Immunosorbent Assay Osteoarthritis Knee Injuries Pharmacology Joint injury Rheumatology Endopeptidases Synovial Fluid medicine Synovial fluid Effective treatment Animals Humans Orthopedics and Sports Medicine Aggrecans Aggrecan Aggrecanase business.industry Joint instability medicine.disease musculoskeletal system Surgery Rats Disease Models Animal Rats Inbred Lew business Biomarkers |
| Zdroj: | Osteoarthritis and cartilage. 19(3) |
| ISSN: | 1522-9653 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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