title: Growth-related oncogene alpha induction of apoptosis in osteoarthritis chondrocytes.
abstract: OBJECTIVE
  To evaluate the apoptotic effect of the chemokine growth-related oncogene alpha (GROalpha), which we recently reported to be up-regulated in osteoarthritis (OA) chondrocytes. Chondrocyte apoptosis is considered to be a major determinant of cartilage damage in OA, a disease resulting from the aberrant production of inflammatory mediators (cytokines and chemokines) and effectors (matrix metalloproteinases and reactive oxygen and nitrogen species) by chondrocytes.
  
  
  METHODS
  We investigated the apoptotic effect of GROalpha on isolated human cells and on in vitro-cultured cartilage explants by conventional methods (morphology, detection of DNA fragmentation in situ and in solution, exposure of phosphatidylserine) and by analysis of "early" biochemical events (plasma membrane depolarization, activation of caspase 3, and phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase).
  
  
  RESULTS
  We clearly demonstrated that GROalpha was able to initiate a series of morphologic, biochemical, and molecular changes that led to chondrocyte apoptosis. Moreover, we found that additional signals delivered from the extracellular matrix (ECM) were essential in the control of chondrocyte susceptibility to GROalpha-induced apoptosis, since cell death was detected only when cells were stimulated after reestablishment of their proper interactions with the ECM, or in cartilage explant samples with reduced ECM, as indicated by decreased Safranin O staining.
  
  
  CONCLUSIONS
  GROalpha can induce apoptosis in articular chondrocytes, and the induction is dependent upon additional signals from the ECM. These findings are relevant to understanding the pathogenesis of OA, in view of the availability of the GROalpha chemokine in the joint space in the course of this rheumatic disease.
authors.affiliation: IRCCS Istituti Ortopedici Rizzoli, Bologna, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Borzi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Mazzetti
authors.forename: Giorgia
authors.initials: G
authors.lastname: Magagnoli
authors.forename: Samantha
authors.initials: S
authors.lastname: Paoletti
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
authors.forename: Rita
authors.initials: R
authors.lastname: Gatti
authors.forename: Guido
authors.initials: G
authors.lastname: Orlandini
authors.forename: Luca
authors.initials: L
authors.lastname: Cattini
authors.forename: Andrea
authors.initials: A
authors.lastname: Facchini
mesh_terms: D017304:Annexin A5; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D018925:Chemokines / Q000494:pharmacology*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology*; D019902:Chondrocytes / Q000187:drug effects* / Q000502:physiology*; D053938:DNA Fragmentation; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics / Q000503:physiopathology*; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D017304:Annexin A5; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D010718:Phosphatidylserines; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases