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.
Liacini
Abdelhamid
A
Département de Médecine and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame du CHUM, Montréal, Québec, Canada.
Sylvester
Judith
J
Li
Wen Qing
WQ
Zafarullah
Muhammad
M
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