Abstract
We have investigated the effects of a carbon monoxide-releasing molecule, tricarbonyldichlororuthenium(II) dimer (CORM-2), on catabolic processes in human osteoarthritis (OA) cartilage and chondrocytes activated with interleukin-1β. In these cells, proinflammatory cytokines induce the synthesis of matrix metalloproteinases (MMPs) and aggrecanases, including members of a disintegrin and metalloproteinase with thrombospondin domain (ADAMTS) family, which may contribute to cartilage loss. CORM-2 down-regulated MMP-1, MMP-3, MMP-10, MMP-13, and ADAMTS-5 in OA chondrocytes, and it inhibited cartilage degradation. These effects were accompanied by increased aggrecan synthesis and collagen II expression in chondrocytes. Our results also indicate that the inhibition of extracellular signal-regulated kinase 1/2 and p38 activation by CORM-2 may contribute to the maintenance of extracellular matrix homeostasis. These observations suggest that CORM-2 could exert chondroprotective effects due to the inhibition of catabolic activities and the enhancement of aggrecan synthesis.
Footnotes
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This work was supported by Grants SAF2004-03835 (Ministerio de Educación y Ciencia-Fondo Europeo de Desarrollo Regional) and ACOMP2007/066 (Generalitat Valenciana). J.M. thanks Spanish Ministerio de Educación y Ciencia for a fellowship.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.134650.
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ABBREVIATIONS: OA, osteoarthritis; MMP, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin domain; IL, interleukin; CO-RM, carbon monoxide-releasing molecule; HO-1, heme oxygenase-1; CORM-2, tricarbonyldichlororuthenium(II) dimer; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; DMEM, Dulbecco's modified Eagle's medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PCR, polymerase chain reaction; CT, cycle threshold; ELISA, enzyme-linked immunosorbent assay; MAPK, mitogen-activated protein kinase.
- Received November 23, 2007.
- Accepted January 11, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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