Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac.
OBJECTIVE
To compare the effect of celecoxib with that of a classic non-steroidal anti-inflammatory drug (NSAID) on synovial inflammation and on the synovial expression of proinflammatory genes in patients with knee osteoarthritis (OA).


METHODS
30 patients with severe knee OA scheduled for total knee replacement surgery were included in a 3 month clinical trial. They were randomised to two groups: patients treated with celecoxib (CBX) (200 mg/24 h) and patients treated with aceclofenac (ACF) (100 mg/12 h). Those patients with OA who did not want to be treated with NSAIDs served as a control group. During knee surgery, synovial fluid (SF) and synovial membrane (SM) were collected. A SM specimen was fixed and embedded in paraffin and another part was frozen for molecular biology studies.


RESULTS
At the end of study both CBX and ACF treated patients showed a significant improvement in pain and knee function compared with controls. Both drugs significantly reduced prostaglandin E(2) (PGE(2)) SF concentration and down regulated COX-2 mRNA and protein expression at the SM. However, synovial macrophage infiltration (CD68 antigen staining) and expression of proinflammatory mediators, such as interleukin 1beta and tumour necrosis factor alpha, were decreased only by CBX treatment.


CONCLUSIONS
Both drugs improved joint pain and function, inhibited SF PGE(2) concentration, and induced a decrease in synovial COX-2 expression and synthesis not related to the tissue inflammatory status. These data suggest that PGE(2) blocking agents may decrease PGE(2) production not only by direct COX-2 inhibition but also by down regulating COX-2 expression and synthesis. However, CBX and ACF appear to have different anti-inflammatory profiles in controlling OA synovial macrophage infiltration and proinflammatory expression.
Servicio de Reumatología, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
M A
MA
Alvarez-Soria
R
R
Largo
J
J
Santillana
O
O
Sánchez-Pernaute
E
E
Calvo
M
M
Hernández
J
J
Egido
G
G
Herrero-Beaumont
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D003864:Depression, Chemical; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics; D007719:Knee Joint; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D020370:Osteoarthritis, Knee / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D000097382:CD68 Molecule
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004008:Diclofenac; D015232:Dinoprostone; D007375:Interleukin-1; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C056498:aceclofenac