title: Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes -- possible pathogenic role in osteoarthritis.
abstract: OBJECTIVE
  Degradative enzymes, such as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinases (MMP), play key roles in development of osteoarthritis (OA). We investigated if crosstalk between subchondral bone osteoblasts (SBO) and articular cartilage chondrocytes (ACC) in OA alters the expression and regulation of ADAMTS5, ADAMTS4, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-13, and also tested the possible involvement of mitogen-activated protein kinase (MAPK) signaling pathway during this process.
  
  
  METHODS
  ACC and SBO were isolated from normal and OA patients. An in vitro coculture model was developed to study the regulation of ADAMTS and MMP under normal and OA joint crosstalk conditions. The MAPK-ERK inhibitor PD98059 was applied to delineate the involvement of specific pathways during this interaction process.
  
  
  RESULTS
  Indirect coculture of OA SBO with normal ACC resulted in significantly increased expression of ADAMTS5, ADAMTS4, MMP-2, MMP-3, and MMP-9 in ACC, whereas coculture of OA ACC led to increased MMP-1 and MMP-2 expression in normal SBO. Upregulation of ADAMTS and MMP under these conditions was correlated with activation of the MAPK-ERK1/2 signaling pathway, and addition of the MAPK-ERK inhibitor PD98059 reversed the overexpression of ADAMTS and MMP in cocultures.
  
  
  CONCLUSIONS
  These results add to the evidence that in human OA, altered bidirectional signals between SBO and ACC significantly influence the critical features of both cartilage and bone by producing abnormal levels of ADAMTS and MMP. We have demonstrated for the first time that this altered crosstalk was mediated by the phosphorylation of MAPK-ERK1/2 signaling pathway.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Campus, Brisbane, Queensland 4059, Australia. i.prasadam@qut.edu.au
authors.forename: Indira
authors.initials: I
authors.lastname: Prasadam
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000503:physiopathology*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011348:Procollagen N-Endopeptidase / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D020782:Matrix Metalloproteinases; D011348:Procollagen N-Endopeptidase; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one