title: Collagenase 3 production by human osteoarthritic chondrocytes in response to growth factors and cytokines is a function of the physiologic state of the cells.
abstract: OBJECTIVE
  We investigated the response of human osteoarthritic (OA) chondrocytes, in terms of collagenase 3 production, to growth factors and cytokines involved in the anabolism and catabolism of articular cartilage, and explored the major signaling pathways leading to its up-regulation.
  
  
  METHODS
  Human OA chondrocytes were treated with the following factors: the proinflammatory cytokine interleukin-1beta (IL-1beta), the growth factors basic fibroblast growth factor (bFGF), platelet-derived growth factor BB (PDGF-BB), parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), transforming growth factor gamma1 (TGFbeta1), and TGFbeta2, the protein kinase (PK) activator antagonists for PKC, PKA, and PKG pathways, and phospholipase A2 and tyrosine kinases, as well as the antiinflammatory cytokines IL-4, IL-10, and IL-13. Collagenase 3 expression and synthesis were determined. Comparison was made with collagenase 1.
  
  
  RESULTS
  The human OA chondrocyte population could be divided into 2 categories: the L chondrocytes, showing low collagenase 3 basal synthesis levels and high sensitivity to IL-1beta stimulation; and the H chondrocytes, high collagenase 3 basal synthesis levels and low IL-1beta inducibility. In L chondrocytes, all growth factors stimulated collagenase 3 production. In H chondrocytes, PTH, IGF-1, and TGFbeta had little or no impact; bFGF slightly stimulated it and PDGF-BB showed the same pattern as in the L chondrocytes. The effects of all growth factors, except TGFbeta, on collagenase 1 synthesis followed those of collagenase 3, albeit to a higher degree. Interestingly and unlike collagenase 3, the effects of TGFbeta on collagenase 1 could not be related to the state of the cells, but rather, depended on the isoform. Indeed, TGFbeta2 did not induce collagenase 1 synthesis, whereas TGFbeta1 stimulated it. Among the PK activators tested, phorbol myristate acetate was the strongest inducer, suggesting a major involvement of the PKC pathway. IL-13 inhibited collagenase 3 production, IL-4 had little effect, and IL-10 had none.
  
  
  CONCLUSIONS
  This study shows that collagenase 3 production in human OA chondrocytes depends on the physiologic state of the cell. TGFbeta might be responsible for the change in cells from the L to the H state. Importantly, our in vitro data implicate TGFbeta2 as a possible in vivo agent capable of specifically triggering collagenase 3 production over that of collagenase 1 in OA cartilage.
authors.affiliation: Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Tardif
authors.forename: J P
authors.initials: JP
authors.lastname: Pelletier
authors.forename: M
authors.initials: M
authors.lastname: Dupuis
authors.forename: C
authors.initials: C
authors.lastname: Geng
authors.forename: J M
authors.initials: JM
authors.lastname: Cloutier
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017364:Collagenases / Q000096:biosynthesis*; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D006133:Growth Substances; D016212:Transforming Growth Factor beta; D011493:Protein Kinase C; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate