P. J. T. Koshy1, Caroline J. Lundy2, Andrew D. Rowan1, Sarah Porter2, Dylan R. Edwards2, Aileen Hogan2, Ian M. Clark2, Timothy E. Cawston1
1Univ. of Newcastle, Newcastle-upon-Tyne, UK#TAB#
2Univ. of East Anglia, Norwich, UK#TAB#
Tóm tắt
AbstractObjectivePrevious studies have reported elevated levels of interleukin‐1 (IL‐1) and oncostatin M (OSM) in rheumatoid joints, as well as the synergistic degradation of human articular cartilage by this cytokine combination. The present study was undertaken to investigate the ability of IL‐1 and OSM to modulate gene expression of matrix metalloproteinase (MMP), ADAM, and ADAM‐TS (ADAM with thrombospondin motifs) family members in human chondrocytes.MethodsT/C28a4 human chondrocytes were stimulated for 2–48 hours with IL‐1 and/or OSM. Total RNA was harvested, reverse transcribed, and assessed by real‐time polymerase chain reaction for the expression of various MMP, ADAM, and ADAM‐TS messenger RNAs (mRNA). Results were normalized to 18S ribosomal RNA.ResultsIL‐1 and OSM synergized to markedly induce the expression of the collagenases MMP‐1, MMP‐8, and MMP‐13 as well as MMP‐3, an activator of proMMPs. Expression of mRNA for MMPs 1, 3, and 13 was induced early, whereas that of MMP‐8 mRNA occurred late. Gene expression of MMP‐14, an MMP that degrades collagen and activates proMMP‐13, was elevated by this combination. IL‐1 and OSM also synergized to induce gene expression of the aggrecanase ADAM‐TS4, but not ADAM‐TS5.ConclusionThese data indicate that the potent cartilage‐degrading properties of the combination of IL‐1 and OSM are potentially mediated by a synergistic induction of the aggrecan‐degrading enzyme ADAM‐TS4 and the collagen‐degrading enzymes MMP‐1, MMP‐8, MMP‐13, and MMP‐14, although differences in the magnitude of response and in the time course of induction were observed. A role for MMPs 3 and 14 in the activation of proMMPs may also be implicated.
