Document Detail


Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid.
MedLine Citation:
PMID:  16927387     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.
Authors:
David R Johnson; Judith A Stebulis; Ronald G Rossetti; Sumner H Burstein; Robert B Zurier
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular biochemistry     Volume:  100     ISSN:  0730-2312     ISO Abbreviation:  J. Cell. Biochem.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-27     Completed Date:  2007-02-28     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8205768     Medline TA:  J Cell Biochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  184-90     Citation Subset:  IM    
Copyright Information:
2006 Wiley-Liss, Inc.
Affiliation:
Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antirheumatic Agents / pharmacology,  therapeutic use*
Arthritis, Experimental / drug therapy,  pathology
Cartilage / metabolism,  pathology
Cells, Cultured
Disease Models, Animal
Embryo, Mammalian
Fibroblasts / metabolism
Humans
Interleukin-1alpha / antagonists & inhibitors,  physiology
Matrix Metalloproteinases / antagonists & inhibitors*,  secretion
Mice
Mice, Knockout
PPAR gamma / genetics,  metabolism*
Rats
Synovial Fluid / cytology
Tetrahydrocannabinol / analogs & derivatives*,  pharmacology,  therapeutic use
Tumor Necrosis Factor-alpha / physiology
Grant Support
ID/Acronym/Agency:
R01 DA 13691/DA/NIDA NIH HHS; T32 AR07572/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Antirheumatic Agents; 0/Interleukin-1alpha; 0/PPAR gamma; 0/Tumor Necrosis Factor-alpha; 0/ajulemic acid; 1972-08-3/Tetrahydrocannabinol; EC 3.4.24.-/Matrix Metalloproteinases

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