title: Pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, upregulates MMP-1 and MMP-13 in IL-1beta-stimulated rheumatoid arthritis fibroblast-like synoviocytes.
abstract: Activated NF-kappaB plays an important role in the expression of matrix metalloproteinase (MMP)-1 and MMP-13 in rheumatoid arthritis and osteoarthritis. The objective of this study was to determine the effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) on the expression of MMPs in IL-1beta-stimulated fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis patients. FLSs were treated with IL-1beta (10 ng/ml) for 24 h in the presence or absence of PDTC. The level of MMP-1 and MMP-13 increased in response to PDTC in time- and dose-dependent manners in IL-1beta-stimulated FLSs; the expressions of IL-6 and vascular endothelial growth factor (VEGF) decreased in a PDTC concentration-dependent manner. However, PDTC-mediated repression of IL-6 and VEGF expression was not observed in TNF-alpha-stimulated rheumatoid arthritis FLSs. In contrast, other NF-kappaB inhibitors, such as fenofibrate, N-acetylcysteine and MG132, decreased MMP expression in IL-1beta-stimulated FLSs. The stimulatory effect of PDTC on MMP expression was not mimicked by specific inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. Treatments with 100 muM PDTC did not inhibit the phosphorylation of p-ERK1/2, p-P38, and p-JNK, or the transnuclear migration of NF-kappaB through degradation of IkappaB-alpha in IL-1beta-stimulated FLSs. These results suggest that the increase of MMP expression may occur in a stimuli-specific manner or by an NF-kappaB independent mechanism. Therefore, therapeutic NF-kappaB inhibitors should be thoroughly studied before their clinical use in treating rheumatoid arthritis, as undesirable genes may be upregulated through unknown mechanisms, possibly resulting in worse symptoms.
authors.affiliation: East-West Bone and Joint Research Institute, East-West Neo Medical Center, Kyung Hee University, Gangdong-Gu, Seoul, Republic of Korea. labrea46@yahoo.co.kr
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Da Hee
authors.initials: DH
authors.lastname: Oh
authors.forename: Hyun Mi
authors.initials: HM
authors.lastname: Choi
authors.forename: Jun Soo
authors.initials: JS
authors.lastname: Bang
authors.forename: Chun Jeih
authors.initials: CJ
authors.lastname: Ryu
authors.forename: Jung Hoe
authors.initials: JH
authors.lastname: Kim
authors.forename: Myung Chul
authors.initials: MC
authors.lastname: Yoo
authors.forename: Hyung-In
authors.initials: HI
authors.lastname: Yang
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010003:Osteoarthritis / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1