title: Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown.
abstract: OBJECTIVE
  To determine whether other glycoprotein 130 (gp130) binding cytokines can mimic the effects of oncostatin M (OSM) in acting synergistically with interleukin-1alpha (IL-1alpha) to induce cartilage collagen breakdown and collagenase expression, and to determine which receptors mediate these effects.
  
  
  METHODS
  The release of collagen and proteoglycan was assessed in bovine and human cartilage explant cultures. Messenger RNA (mRNA) and protein production from immortalized human chondrocytes (T/C28a4) was analyzed by Northern blotting and specific enzyme-linked immunosorbent assays. Collagenase activity was measured by bioassay. Cell surface receptors were detected by flow cytometry.
  
  
  RESULTS
  OSM in combination with IL-1alpha caused a rapid synergistic induction of matrix metalloproteinase 1 mRNA, which was sustained over a 72-hour period. Flow cytometric analyses detected both the OSM-specific receptor and the gp130 receptor at the chondrocyte cell surface, but failed to detect the leukemia inhibitory factor receptor (LIFR). Cartilage degradation assays revealed that, of the gp130 binding cytokines, only OSM and IL-6, in the presence of its soluble receptor (sIL-6R), were able to act synergistically with IL-1alpha to promote collagen release.
  
  
  CONCLUSIONS
  This study demonstrates that IL-6 can mimic OSM in synergizing with IL-1alpha to induce chondrocyte-mediated cartilage collagen breakdown and collagenase production. In order to have this effect, IL-6 requires the presence of its soluble receptor. The apparent absence of LIFR explains why other gp130 binding cytokines do not act in synergy with IL-1alpha. Since OSM, IL-6, and sIL-6R levels have all been shown to be elevated in the rheumatoid joint, our findings suggest that these cytokines may be key mediators of cartilage collagen catabolism in the inflammatory arthritides.
authors.affiliation: Rheumatology, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Rowan
authors.forename: P J
authors.initials: PJ
authors.lastname: Koshy
authors.forename: W D
authors.initials: WD
authors.lastname: Shingleton
authors.forename: B A
authors.initials: BA
authors.lastname: Degnan
authors.forename: J K
authors.initials: JK
authors.lastname: Heath
authors.forename: A B
authors.initials: AB
authors.lastname: Vernallis
authors.forename: J R
authors.initials: JR
authors.lastname: Spaull
authors.forename: P F
authors.initials: PF
authors.lastname: Life
authors.forename: K
authors.initials: K
authors.lastname: Hudson
authors.forename: T E
authors.initials: TE
authors.lastname: Cawston
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002358:Cartilage, Articular / Q000166:cytology; D002417:Cattle; D002461:Cell Line, Transformed; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism*; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D017370:Interleukin-11 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D007375:Interleukin-1; D017370:Interleukin-11; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D019715:Tissue Inhibitor of Metalloproteinase-1; D053683:Oncostatin M; D019716:Tissue Inhibitor of Metalloproteinase-2; D050822:Cytokine Receptor gp130; D003094:Collagen; C092073:cardiotrophin 1; D020781:Matrix Metalloproteinase 1