Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Abstract

Objective. To evaluate the effects of LG100268 (LG268), a synthetic ligand for the nuclear hormone receptor retinoid X receptor, on the expression of matrix metalloproteinase 1 (MMP-1) and MMP-13 induced by proinflammatory cytokines in a chondrocyte model.Methods. SW-1353 human chondrosarcoma cells were used to study the effects of LG268 on interleukin-1␤ (IL-1␤)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcriptionpolymerase chain reaction, and protein levels were determined by Western blot analysis. Collagen degradation was determined by an in vitro matrix destruction assay. The effects of LG268 on nuclear protein binding and histone acetylation were determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively.Results.LG268 treatment specifically antagonized the IL-1␤-mediated induction of MMP-1 and MMP-13 heterogeneous nuclear RNA, messenger RNA, and protein. The inhibitory effect of LG268 was found to be due to a decrease in the rate of MMP-1 and MMP-13 transcription.LG268 treatment also prevented the in vitro degradation of a type I collagen matrix by IL-1␤-treated SW-1353 cells. The inhibitory effect of LG268 on MMP-1 and MMP-13 transcription appears to be mediated, at least in part, through modulation of histone modification in regions of the MMP-1 and MMP-13 promoters that contain binding sites for activator protein 1 transcription factors.Conclusion. These data indicate that LG268 treatment selectively inhibits inflammatory cytokineinduced production of MMP-1 and MMP-13 at the level of gene transcription and blocks collagen destruction by proinflammatory cytokine-stimulated chondrocytic cells. This study is among the first to describe how rexinoids affect gene expression, and the findings suggest that the rexinoid class of compounds may have a future role in preventing the irreversible collagen destruction seen in the arthritides.The destruction of joint tissues that is a hallmark of rheumatoid arthritis (RA) and osteoarthritis (OA) is mediated largely by members of the matrix metalloproteinase (MMP) family of enzymes (1-3). At low expression levels, these zinc-dependent endopeptidases maintain connective tissue homeostasis in a wide range of biologic functions (4). However, abnormally high levels of MMP expression have been linked to multiple pathologic states, including tumor invasion, atherosclerosis, and the arthritides (4). In humans, the MMP family currently encompasses 23 unique members, which degrade all constituents of the extracellular matrix (ECM) (5). The MMPs can be subdivided into 6 main classes (1,4,5), consisting of the collagenases (MMPs 1, 8, and 13), the gelatinases (MMPs 2 and 9), the stromelysins (MMPs 3, 10, and 11), the matrilysins (MMPs 7 and 26), the membrane-type MMPs (MMPs 14,15,16,17,24,and 25), and a diverse subgroup.The collagenase subgroup is unique in its ability to cleave fibrillar collagens, and their enzymatic activity represents a rate-limiting step...

Epigenetic regulation of proMMP-1 expression in the HT1080 human fibrosarcoma cell line

“…For instance, interleukin-1β, UV radiations or phorbol esters, increase proMMP-1 gene expression through histone posttranslational modifications (22,29). In this study we observed that accumulation of hyperacetylated histones is not a sufficient trigger to enhance either proMMP-1 gene expression or chromatin global decondensation in HT1080 fibrosarcoma cells.…”

Distal Interleukin-1β (IL-1β) Response Element of Human Matrix Metalloproteinase-13 (MMP-13) Binds Activator Protein 1 (AP-1) Transcription Factors and Regulates Gene Expression

“…Treatment of primary chondrocytes and cell lines with IL-1␤ dramatically increases transcription of MMP-13, with a concordant increase in collagen destruction (6 -8). AP-1 response elements have been identified in the proximal promoter region of MMP-13, through sequence analysis and by reporter assays utilizing both stably and transiently transfected reporter constructs (5,9,10). A puzzling aspect of these studies, however, is that reporter constructs driven by the MMP-13 proximal promoter often do not mimic the expression pattern of endogenous MMP-13 (5, 9, 11).…”

The Anti-Cancer Effect of a Novel Nutrient Mixture by Inhibiting MMPs Expression, Invasion and Inducing Apoptosis in Chondrosarcoma Cell Line SW-1353

“…In another study, Elliot's group also showed that synthetic triterpenoid, CDDO, inhibited IL-1 induced MMP-1 and MMP-13 expression in SW-1353 cells (Elliott et al, 2003). While Burrage et al evaluated the effect of synthetic ligand LG 100268 for nuclear hormone receptor and it selectively inhibit IL-1 and stimulate MMP-1 and MMP-13 (Burrage et al, 2007).…”