Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model.
Oncostatin M (OSM) is an interleukin (IL)-6 family cytokine that we have previously shown can synergize with a number of proinflammatory cytokines to promote the release of collagen from cartilage in explant culture. However, the effects of this potent cytokine combination in vivo are not known. Using adenoviral gene transfer, we have overexpressed murine IL-1 (AdmIL-1) and murine OSM (AdmOSM) intraarticularly in the knees of C57BL/6 mice. Histological analyses indicated marked synovial hyperplasia and inflammatory cell infiltration for both AdmIL-1 and AdmOSM but not in control joints. This inflammation was even more pronounced for the AdmIL-1+AdmOSM combination with evidence of cartilage and bone destruction. Significant loss of both proteoglycan and collagen was also seen for this combination, and immunohistochemistry revealed an increased expression of matrix metalloproteinases (MMPs) with decreased tissue inhibitor of metalloproteinases (TIMPs) in both articular cartilage and synovium. Similar expression profiles for MMPs/TIMPs were found in IL-1+OSM-stimulated human articular chondrocytes. Taken together, these data confirm that, in vivo, OSM can exacerbate the effects of IL-1 resulting in inflammation and tissue destruction characteristic of that seen in rheumatoid arthritis. We provide further evidence to implicate the up-regulation of MMPs as a key factor in joint pathology.
Rowan
Andrew D
AD
Department of Rheumatology, the School of Clinical Medical Sciences, The Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom. A.D.Rowan@ncl.ac.uk
Hui
Wang
W
Cawston
Tim E
TE
Richards
Carl D
CD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000235:genetics* / Q000502:physiology; D007592:Joint Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics* / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection / Q000379:methods
D007375:Interleukin-1; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; D053683:Oncostatin M; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020784:Matrix Metalloproteinase 8