Nuclear receptor ligands LG268 and rosiglitazone inhibit collagen destruction by chondrocytic cells stimulated with interleukin‐1 beta

Abstract

Matrix metalloproteinase‐1 (MMP‐1) and MMP‐13 mediate cartilage destruction in arthritis. Our objective was to evaluate the inhibition of IL‐1β‐induced MMP‐1 and ‐13 expression in SW1353 chondrocytic cells by retinoid x receptor (RXR) ligand LG100268 (LG268), and peroxisome proliferator‐activated receptor gamma (PPARγ??ligand rosiglitazone (rosi).We pretreated SW1353 cells with LG268 and/or rosi, then added IL‐1ß (1 ng/ml). MMP‐1 and ‐13 hnRNA and mRNA was measured by realtime RT‐PCR, and cells were embedded in collagen to measure collagenolysis. Chromatin immunoprecipitation (ChIP) detected PPARγ?and acetylated histone H4 (AcH4) at the Activator Protein‐1/PPARγ response element (AP‐1/PPRE) in the MMP‐1 and ‐13 promoters. Modification of PPARγ and RXR by small ubiquitin‐like modifier (SUMO) was measured by IP and Western blot.LG268 and rosi reduced MMP‐1 and ‐13 mRNA, AcH4 at the AP‐1/PPRE, and collagen destruction, and combined rosi/LG268 treatment had an additive effect. Treatment with rosi or LG268 led to SUMOylation of PPARγ and RXR, respectively, and induced "cross SUMOylation" of the other partner in the PPARγ:RXR heterodimer. Unexpectedly, ChIP indicated increased PPARγ at the AP‐1/PPRE in IL‐1β‐treated vs. untreated cells, while rosi and LG268 had little effect.LG268 and rosi inhibit IL‐1ß‐induced MMP‐1 and ‐13, and reduce collagen destruction in vitro, likely by multiple mechanisms.Funding SupportACS: T32‐AR‐07576; PSB: T32‐AI‐07363; ACS, PSB, CEB: NIH ‐AR‐26599, 2.