title: Tumor necrosis factor alpha activation of the apoptotic cascade in murine articular chondrocytes is associated with the induction of metalloproteinases and specific pro-resorptive factors.
abstract: OBJECTIVE
  Tumor necrosis factor alpha (TNFalpha) blockade provides substantive reduction of the symptoms of rheumatoid arthritis (RA). While the biologic actions of TNFalpha have been well characterized in immune and synovial cells, which are known to be major contributors to the progression of cartilage destruction in RA, the current studies were designed to assess the direct effects of TNFalpha on chondrocytes.
  
  
  METHODS
  We examined the expression of several groupings of messenger RNA (mRNA) that define key biologic pathways that have previously been associated with either the general actions of TNFalpha or cartilage destruction, in murine articular chondrocytes isolated from wild-type mice and TNFalpha receptor-null (p55/p75(-/-)) mice.
  
  
  RESULTS
  TNFalpha induced the expression of multiple mRNA that facilitate apoptosis and lead to apoptosis-induced cell death. The induction of apoptosis was accompanied by the increased expression of several factors involved in the regulation of skeletal tissue proteolysis and resorption. Quantitative increases from 2-fold to >10-fold were seen for inducible nitric oxide synthase, matrix metalloproteinase 3, macrophage colony-stimulating factor, and osteoprotegerin mRNA expression. The dependence of the induction of these mRNA on TNFalpha was confirmed by comparison with the effects of TNFalpha on chondrocytes isolated from receptor-null mice.
  
  
  CONCLUSIONS
  These findings demonstrate that TNFalpha alters the expression of a complex array of genes within murine chondrocytes that contribute to the destruction of joint surfaces, independent of its actions on synovial and immune cells. Further studies are needed to clarify the biologic actions of TNFalpha in human cartilage cells.
authors.affiliation: Boston University Medical Center, Boston, Massachusetts, USA.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lehmann
authors.forename: Cory
authors.initials: C
authors.lastname: Edgar
authors.forename: Cameron
authors.initials: C
authors.lastname: Sadeghi
authors.forename: Andrew
authors.initials: A
authors.lastname: Hou
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Einhorn
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D053244:Osteoprotegerin; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019278:Matrix Metalloproteinase 3