Inhibition of synoviocyte collagenase gene expression by adenosine receptor stimulation

Arthritis Rheum. 1996 Jun;39(6):923-30. doi: 10.1002/art.1780390608.


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.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine-5'-(N-ethylcarboxamide)
  • Base Sequence
  • Cells, Cultured
  • Collagenases / metabolism*
  • Cyclic AMP / physiology
  • Humans
  • Interleukin-1 / pharmacology
  • Matrix Metalloproteinase 3
  • Metalloendopeptidases / drug effects
  • Metalloendopeptidases / metabolism
  • Molecular Sequence Data
  • Purinergic P1 Receptor Agonists*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Receptors, Purinergic P1 / chemistry
  • Synovial Membrane / cytology
  • Synovial Membrane / enzymology*
  • Time Factors


  • Interleukin-1
  • Purinergic P1 Receptor Agonists
  • RNA, Messenger
  • Receptors, Purinergic P1
  • Adenosine-5'-(N-ethylcarboxamide)
  • Cyclic AMP
  • Collagenases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Adenosine