title: Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases (COX) and are widely used for post-trauma musculoskeletal analgesia. In animal models, NSAIDs have been reported to delay fracture healing and cause non-union, possibly due to the drug-induced inhibition of osteoblast recruitment and differentiation. To further investigate the cellular effects of these drugs in the context of bone healing, we examined the effects of COX-1 inhibitor indomethacin and COX-2 inhibitors, parecoxib and NS398 on osteoclast and osteoblast differentiation and activity in vitro. We discovered that all tested COX-inhibitors significantly inhibited osteoclast differentiation, by 93%, 94% and 74% of control for 100 microM indomethacin, 100 microM parecoxib and 3 microM NS398, respectively. Furthermore, inhibition of COX-2 reduced also the resorption activity of mature osteoclasts. All tested COX-inhibitors also significantly inhibited osteoblast differentiation from human mesenchymal stem cells. Simultaneously, the number of adipocytes was significantly increased. The adipocyte covered areas in the cultures with 1 microM indomethacin, 1 microM parecoxib and 3 microM NS398 were 9%, 29% and 24%, respectively, as compared with 6% in the control group. This data suggests that COX-2 inhibition disturbs bone remodelling by inhibiting osteoclast differentiation and diverting stem cell differentiation towards adipocyte lineage instead of osteoblast lineage. In conclusion, our results further suggest cautious use of COX-2 inhibitors after osseous trauma.
authors.affiliation: Clinical Research Centre, Department of Surgery, University of Oulu, Finland. maarit.kellinsalmi@oulu.fi
authors.forename: Maarit
authors.initials: M
authors.lastname: Kellinsalmi
authors.forename: Vilhelmiina
authors.initials: V
authors.lastname: Parikka
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Teuvo
authors.initials: T
authors.lastname: Hentunen
authors.forename: Hannu-Ville
authors.initials: HV
authors.lastname: Leskelä
authors.forename: Siri
authors.initials: S
authors.lastname: Lehtonen
authors.forename: Katri
authors.initials: K
authors.lastname: Selander
authors.forename: Kalervo
authors.initials: K
authors.lastname: Väänänen
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology; D007555:Isoxazoles / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D009578:Nitrobenzenes / Q000009:adverse effects / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C409945:parecoxib; D007213:Indomethacin