Rofecoxib regulates the expression of genes related to the matrix metalloproteinase pathway in humans: implication for the adverse effects of cyclooxygenase-2 inhibitors.
BACKGROUND
Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins contribute to acute inflammation and pain, as well as resolution of inflammation; inhibition of COX-2 results in persistence of inflammation. Because matrix metalloproteinases (MMPs) play an essential role in inflammatory tissue injury and their activity is regulated by COX-2-derived prostaglandin E2, we evaluated whether COX-2 inhibition is associated with MMP overexpression during acute inflammation.


METHODS
A total of 102 oral mucosal biopsy specimens were taken from 51 healthy volunteers who required extraction of impacted third molars. Subjects randomly received either rofecoxib (50 mg daily), ibuprofen (400 mg 4 times per day), or placebo 90 minutes before surgery and up to 48 hours after surgery. Total ribonucleic acid extracted from each biopsy specimen was used to analyze changes in gene expression related to the MMP pathway after tissue injury and drug treatments by use of microarray and quantitative real-time polymerase chain reaction in this clinical model of acute inflammation.


RESULTS
Following tissue injury, rofecoxib increased the expression of genes associated with degradation of the extracellular matrix, including MMP-1 (64.7 +/- 6.5, P = .010), MMP-3 (41.7 +/- 4.8, P = .007), PLAT (encoding tissue plasminogen activator) (10.9 +/- 4.6, P = .032), and IL8 (encoding interleukin 8) (8.3 +/- 6.7, P = .020), and decreased the expression of TIMP3 (encoding tissue inhibitor of metalloproteinase 3) (6.2 +/- 2.8, P = .027). Ibuprofen produced similar effects on the expression of MMP-1 (23.4 +/- 5.0, P = .016) and MMP-3 (26.3 +/- 4.2, P = .003). In contrast, the expression of these genes was not statistically changed after tissue injury in the placebo group. The microarray data were in concordance with the changes in gene expression confirmed by quantitative real-time polymerase chain reaction.


CONCLUSIONS
These findings provide evidence at the transcriptional level that inhibition of COX-2, in the presence of acute inflammation, induces changes in gene expression related to the MMP pathway. These changes may contribute to the adverse effects attributed to COX-2 inhibition by interfering with resolution of inflammation.
Pain and Neurosensory Mechanisms Branch and Biostatistics Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Xiao-Min
XM
Wang
Tian-Xia
TX
Wu
Yun-Sil
YS
Lee
Raymond A
RA
Dionne
D000293:Adolescent; D000328:Adult; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000235:genetics; D011184:Postoperative Period; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000187:drug effects / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000235:genetics
D052246:Cyclooxygenase 2 Inhibitors; D016209:Interleukin-8; D007783:Lactones; D061965:Matrix Metalloproteinase Inhibitors; D013450:Sulfones; D019717:Tissue Inhibitor of Metalloproteinase-3; C116926:rofecoxib; D051546:Cyclooxygenase 2; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D007052:Ibuprofen