title: In vitro effects of VA441, a new selective cyclooxygenase-2 inhibitor, on human osteoarthritic chondrocytes exposed to IL-1β.
abstract: The aim of this in vitro study was to examine the possible effect of [2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-3-(2-n-propyloxyethyl)]-1H-pyrrole (VA441), a new selective cyclooxygenase (COX)-2 inhibitor, on human osteoarthritic (OA) chondrocyte cultivated in the presence or absence of interleukin-1β (IL-1β). In particular, we assessed the effects of 1 and 10 μM of VA441, celecoxib, and indomethacin on cell viability, COX-2 and inducible nitric oxide synthase (iNOS) gene expression, prostaglandin E(2) (PGE(2)) production, and nitric oxide (NO) and metalloproteinase-3 (MMP-3) release. Furthermore, we carried out morphological assessment by transmission electron microscopy (TEM). The presence of IL-1β led to a significant increase in PGE(2), MMP-3, and NO production, as well as a significant increase in gene expression of COX-2 and iNOS. All the drugs tested had a statistically significant inhibitory effect on PGE(2) production and gene expression of COX-2 stimulated by IL-1β. VA441 and celecoxib significantly suppressed IL-1β-stimulated MMP-3 and NO and iNOS gene expression in a dose-dependent manner, while indomethacin did not show any significant effect on MMP-3 and NO production or on iNOS gene expression. TEM demonstrated that IL-1β severely alters the structure of chondrocytes; after co-incubation with VA441 or celecoxib, the cells recovered their ultrastructure. Our data suggest that VA441 and celecoxib may have a beneficial effect on chondrocyte metabolism.
authors.affiliation: Department of Clinical Medicine and Immunology, Rheumatology Unit, University of Siena, Italy. fioravanti7@virgilio.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Laura
authors.initials: L
authors.lastname: Tinti
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Pascarelli
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.forename: Antonello
authors.initials: A
authors.lastname: Lamboglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Silvia
authors.initials: S
authors.lastname: Niccolini
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
mesh_terms: D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010003:Osteoarthritis; D011758:Pyrroles / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C577901:2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-3-(2-n-propyloxyethyl)-1H-pyrrole; D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D011758:Pyrroles; D013450:Sulfones; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D015232:Dinoprostone