In Vitro Effects of VA441, a New Selective Cyclooxygenase-2 Inhibitor, on Human Osteoarthritic Chondrocytes exposed to IL-1β

• Published in: Journal of Pharmacological Sciences 2012, Vol.120(1), pp.6-14
• Main Authors: Fioravanti, Antonella, Tinti, Laura, Pascarelli, Nicola Antonio, Capua, Angela Di, Lamboglia, Antonello, Cappelli, Andrea, Biava, Mariangela, Giordani, Antonio, Niccolini, Silvia, Galeazzi, Mauro, Anzini, Maurizio
• Format: Article
• Language: English
• Subjects: Aged; celecoxib; Cell Survival - drug effects; Cells, Cultured; chondrocyte; Chondrocytes - drug effects; Chondrocytes - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 Inhibitors - pharmacology; cyclooxygenase-2 inhibitor; Dinoprostone - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Humans; indomethacin; Interleukin-1beta - pharmacology; Matrix Metalloproteinase 3 - metabolism; Middle Aged; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Osteoarthritis; Pyrroles - pharmacology; Sulfones - pharmacology; VA441
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.12016FP

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 E2 (PGE2) 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 PGE2, 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 PGE2 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 coincubation with VA441 or celecoxib, the cells recovered their ultrastructure. Our data suggest that VA441 and celecoxib may have a beneficial effect on chondrocyte metabolism.