Mithramycin downregulates proinflammatory cytokine-induced matrix metalloproteinase gene expression in articular chondrocytes.
Interleukin-1 (IL-1), IL-17 and tumor necrosis factor alpha (TNF-alpha) are the main proinflammatory cytokines implicated in cartilage breakdown by matrix metalloproteinase (MMPs) in arthritic joints. We studied the impact of an anti-neoplastic antibiotic, mithramycin, on the induction of MMPs in chondrocytes. MMP-3 and MMP-13 gene expression induced by IL-1beta, TNF-alpha and IL-17 was downregulated by mithramycin in human chondrosarcoma SW1353 cells and in primary human and bovine femoral head chondrocytes. Constitutive and IL-1-stimulated MMP-13 levels in bovine and human cartilage explants were also suppressed. Mithramycin did not significantly affect the phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase. Despite effective inhibition of MMP expression by mithramycin and its potential to reduce cartilage degeneration, the agent might work through multiple unidentified mechanisms.
Département de Médecine and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame du CHUM, Montréal, Québec, Canada.
Abdelhamid
A
Liacini
Judith
J
Sylvester
Wen Qing
WQ
Li
Muhammad
M
Zafarullah
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006621:Hip Joint / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D017746:Joint Capsule; D007719:Knee Joint / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D008926:Plicamycin / Q000494:pharmacology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D020782:Matrix Metalloproteinases; D008926:Plicamycin