title: Nonsteroidal antiinflammatory drugs and prostaglandin E(2) modulate the synthesis of osteoprotegerin and RANKL in the cartilage of patients with severe knee osteoarthritis.
abstract: OBJECTIVE
  Although the osteoprotegerin (OPG)/RANK/RANKL system is the main modulator of bone remodeling, it remains unclear whether it is regulated in cartilage during osteoarthritis (OA). The aim of this study was to examine whether nonsteroidal antiinflammatory drug (NSAID) treatment modulates the synthesis of OPG and RANKL in the cartilage of patients with OA, and to investigate whether prostaglandin E(2) (PGE(2)) modifies this system in human OA chondrocytes in culture.
  
  
  METHODS
  A 3-month clinical trial was carried out in 20 patients with severe knee OA, all of whom were scheduled to undergo knee replacement surgery. Ten of these patients were treated with celecoxib, and the other 10 patients, who did not want to be treated, served as the control group. After surgery, cartilage was processed for molecular biology studies. We also used human OA chondrocytes to examine the effects of PGE(2) on OPG/RANKL synthesis, examining which surface receptors were affected by PGE(2).
  
  
  RESULTS
  In patients with OA, celecoxib decreased RANKL synthesis in the cartilage, thereby increasing the OPG:RANKL ratio. In human OA chondrocytes in culture, PGE(2) elicited a dose- and time-dependent increase in the synthesis of RANKL, the extent of which was greater than that of OPG. Confocal microscopy revealed that PGE(2) induced RANKL transport to the cell membrane. Only EP2/EP4 agonists reproduced the effects of PGE(2) on OPG and RANKL induction.
  
  
  CONCLUSIONS
  Long-term NSAID treatment inhibited the resorptive signal synthesized by chondrocytes. In vitro, PGE(2) regulated the expression and release of these key mediators of bone metabolism by articular chondrocytes. The role of OPG/RANK/RANKL in OA cartilage metabolism is still unknown, although the synthesis of these proteins would enable the cartilage to control the activity of subchondral bone cells.
authors.affiliation: Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Moreno-Rubio
authors.forename: Gabriel
authors.initials: G
authors.lastname: Herrero-Beaumont
authors.forename: Lidia
authors.initials: L
authors.lastname: Tardio
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Alvarez-Soria
authors.forename: Raquel
authors.initials: R
authors.lastname: Largo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000068579:Celecoxib; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D053244:Osteoprotegerin; D011720:Pyrazoles; D053245:RANK Ligand; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; C505688:TNFSF11 protein, human; D000068579:Celecoxib; D015232:Dinoprostone