title: Molecular changes in human osteoarthritic cartilage after 3 weeks of oral administration of BAY 12-9566, a matrix metalloproteinase inhibitor.
abstract: OBJECTIVE
  To determine the effect of BAY 12-9566, a matrix metalloproteinase inhibitor, on articular cartilage metabolism in patients with osteoarthritis (OA).
  
  
  METHODS
  Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage.
  
  
  RESULTS
  Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected.
  
  
  CONCLUSIONS
  BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content.
authors.affiliation: Bayer Corporation, West Haven, Connecticut, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leff
authors.forename: Ileana
authors.initials: I
authors.lastname: Elias
authors.forename: Mirela
authors.initials: M
authors.lastname: Ionescu
authors.forename: Agnes
authors.initials: A
authors.lastname: Reiner
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
mesh_terms: D000284:Administration, Oral; D000368:Aged; D053674:Aggrecans; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D037181:Lectins, C-Type; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D009930:Organic Chemicals; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010654:Phenylbutyrates; D011509:Proteoglycans / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D053674:Aggrecans; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D024043:Collagen Type II; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D011509:Proteoglycans; C113281:Bay 12-9566