Regulation of matrix metalloproteinase gene expression by a retinoid X receptor-specific ligand.
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-1beta (IL-1beta)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcription-polymerase 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-1beta-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-1beta-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.


CONCLUSIONS
These data indicate that LG268 treatment selectively inhibits inflammatory cytokine-induced 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.
Burrage
Peter S
PS
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
Huntington
Jonathan T
JT
Sporn
Michael B
MB
Brinckerhoff
Constance E
CE
D001168:Arthritis / Q000188:drug therapy / Q000503:physiopathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D009539:Nicotinic Acids / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology; D047488:Retinoid X Receptors / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology
D006657:Histones; D053583:Interleukin-1beta; D008024:Ligands; D009539:Nicotinic Acids; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D018808:Transcription Factor AP-1; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; C095104:LG 100268