title: Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions.
abstract: OBJECTIVE
  Articular cartilage degeneration in osteoarthritis (OA) involves excessive degradation of extracellular matrix (ECM) and chondrocyte differentiation (hypertrophy). We determined the interrelationship between the extent of collagen cleavage by collagenase, cartilage degeneration, and differentiation related gene expression in patella-femoral condylar cartilages of patients bearing very early focal OA-like articular cartilage lesions.
  
  
  METHODS
  Articular cartilage specimens with very early focal lesions and adjacent normal cartilage from 3 donors were removed at autopsy as full-depth slices cut from the femoral condyle surface that articulates with patella. Slices were divided into sections and used for Mankin grading, examination of collagenase cleavage of type II collagen by ELISA, and gene expression by RT-PCR.
  
  
  RESULTS
  Early focal cartilage degeneration was associated with increased collagenase cleavage of type II collagen. The collagenases metalloproteinase-1 (MMP-1), MMP-14 (MT1-MMP), and aggrecanase ADAMTS-5 (a disintegrin and metalloprotease with thrombospondin motifs) (but not ADAMTS-4); cytokines interleukin 1alpha/beta and tumor necrosis factor-alpha (TNF-alpha); chondrocyte terminal differentiation-related genes COL10A1, MMP-13, MMP-9, Indian hedgehog; and caspase 3 were often upregulated in the vicinity of the lesion. Growth factors associated with growth plate chondrocyte proliferation, namely fibroblast growth factor-2, parathyroid hormone related protein, transforming growth factor (TGF)-beta1/2, as well as the matrix molecules COL2A1 and aggrecan were expressed adjacent to and remote from the lesion. Of all genes only caspase 3 and ADAMTS-5 expression was exclusively seen in association with these early lesions. Elevation of collagenase activity was associated with a frequent elevation of expression of COL10A1, caspase 3, IL-1alpha/beta, MMP-1, and ADAMTS-5, and a decreased expression of Sox-9 (SRY-type high-mobility-group box transcription factor-9), TGF-beta1, TGF-beta2, TNF-alpha, and aggrecan. Other genes showed no observable difference with changes in collagenase activity.
  
  
  CONCLUSIONS
  Very early focal degeneration in knee articular cartilage is accompanied by upregulation of collagenase activity and expression of genes associated with chondrocyte terminal differentiation and matrix degradation. Thus chondrocyte differentiation may be closely related to the very early development of cartilage degeneration such as occurs in OA.
authors.affiliation: Joint Diseases Laboratory, Shriners Hospitals for Children, Montreal, Quebec, Canada. etchetina@shriners.mcgill.ca
authors.forename: Elena V
authors.initials: EV
authors.lastname: Tchetina
authors.forename: Ginette
authors.initials: G
authors.lastname: Squires
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000473:pathology* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000473:pathology* / Q000502:physiology*; D024043:Collagen Type II / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics; D042241:Early Diagnosis; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007719:Knee Joint / Q000473:pathology; D008297:Male; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D015854:Up-Regulation
chemical_list: D024043:Collagen Type II; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D045726:Metalloproteases