title: Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants.
abstract: OBJECTIVE
  MMP-13 is highly upregulated in arthritis and therefore strongly implicated in the pathogenesis of osteoarthritis (OA). Selective inhibition of MMP-13 may provide the desired cartilage degradation protection, while overcoming the musculoskeletal toxicity seen with nonselective inhibition of MMPs.
  
  
  METHODS
  Activity and selectivity of novel MMP-13 inhibitors were determined in enzymatic and collagenase assays. Inhibition kinetics and competitive binding experiments were performed. The inhibition of collagen degradation was studied in cartilage explants from OA patients and in bovine and human articular cartilage systems.
  
  
  RESULTS
  We have identified a new class of very potent and highly selective non-zinc-binding MMP-13 inhibitors. Selective MMP-13 inhibitors completely blocked type II collagen degradation in bovine explants and showed up to 80% inhibition in human OA cartilage.
  
  
  CONCLUSIONS
  These results indicate MMP-13 as the primary collagenase in the human OA cartilage and in the IL-1/OSM-induced cartilage degradation process and suggest that selective MMP-13 inhibitors may be a potential treatment of OA.
authors.affiliation: Alantos Pharmaceuticals AG, Heidelberg, Germany. d.piecha@gmx.de
authors.forename: Dorothea
authors.initials: D
authors.lastname: Piecha
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weik
authors.forename: Heike
authors.initials: H
authors.lastname: Kheil
authors.forename: Gabriele
authors.initials: G
authors.lastname: Becher
authors.forename: Andreas
authors.initials: A
authors.lastname: Timmermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Jaworski
authors.forename: Maren
authors.initials: M
authors.lastname: Burger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000201:enzymology* / Q000473:pathology*; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000201:enzymology / Q000473:pathology*; D046509:Tissue Culture Techniques
chemical_list: D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D053509:Matrix Metalloproteinase 13