OBJECTIVE: To characterize the regulation of matrix metalloproteinases (MMPs) by adenosine. METHODS: Cultured fibroblast-like synoviocytes (FLS) were stimulated with interleukin-1 (IL-1) in the presence or absence of adenosine receptor agonists. Immunoreactive MMPs were measured using specific enzyme-linked immunosorbent assays, and gene expression was assessed by Northern blot analysis. RESULTS: The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) decreased collagenase production by IL-1-stimulated synoviocytes from 196 +/- 28 ng/ml (mean +/- SEM) to 66 +/- 9 ng/ml (P < 0.001). There was minimal effect on stromelysin production (decrease from 107 +/- 16 ng/ml to 97 +/- 15 ng/ml). Selective adenosine receptor agonists implicated the A2b adenosine receptor in this activity, and reverse transcriptase-polymerase chain reaction studies confirmed that FLS express this receptor. Northern blot analysis demonstrated that the mechanism of action was pre-translational since NECA decreased collagenase, but not stromelysin or tissue inhibitor of metalloproteinases 1 (TIMP-1), messenger RNA levels. Cyclic AMP levels were increased by NECA, and a direct adenylate cyclase activator (forskolin) also suppressed collagenase gene expression. These data suggest that cAMP mediates the inhibitory effect of NECA on collagenase production. CONCLUSION: Stimulation of the A2b receptor on FLS decreases collagenase gene expression, with little or no effect on stromelysin and TIMP-1. The combination of antiinflammatory and MMP-regulating properties of adenosine or adenosine-regulating agents suggest that treatment based on this approach might be useful in rheumatoid arthritis.
OBJECTIVE: To characterize the regulation of matrix metalloproteinases (MMPs) by adenosine. METHODS: Cultured fibroblast-like synoviocytes (FLS) were stimulated with interleukin-1 (IL-1) in the presence or absence of adenosine receptor agonists. Immunoreactive MMPs were measured using specific enzyme-linked immunosorbent assays, and gene expression was assessed by Northern blot analysis. RESULTS: The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) decreased collagenase production by IL-1-stimulated synoviocytes from 196 +/- 28 ng/ml (mean +/- SEM) to 66 +/- 9 ng/ml (P < 0.001). There was minimal effect on stromelysin production (decrease from 107 +/- 16 ng/ml to 97 +/- 15 ng/ml). Selective adenosine receptor agonists implicated the A2b adenosine receptor in this activity, and reverse transcriptase-polymerase chain reaction studies confirmed that FLS express this receptor. Northern blot analysis demonstrated that the mechanism of action was pre-translational since NECA decreased collagenase, but not stromelysin or tissue inhibitor of metalloproteinases 1 (TIMP-1), messenger RNA levels. Cyclic AMP levels were increased by NECA, and a direct adenylate cyclase activator (forskolin) also suppressed collagenase gene expression. These data suggest that cAMP mediates the inhibitory effect of NECA on collagenase production. CONCLUSION: Stimulation of the A2b receptor on FLS decreases collagenase gene expression, with little or no effect on stromelysin and TIMP-1. The combination of antiinflammatory and MMP-regulating properties of adenosine or adenosine-regulating agents suggest that treatment based on this approach might be useful in rheumatoid arthritis.
Authors: K Varani; F Vincenzi; A Tosi; M Targa; F F Masieri; A Ongaro; M De Mattei; L Massari; P A Borea Journal: Br J Pharmacol Date: 2010-03-19 Impact factor: 8.739
Authors: Francisco Villarreal; Scott Zimmermann; Lala Makhsudova; Annika C Montag; Mark D Erion; David A Bullough; Bruce R Ito Journal: Mol Cell Biochem Date: 2003-09 Impact factor: 3.396