Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants.
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.
Piecha
Dorothea
D
Alantos Pharmaceuticals AG, Heidelberg, Germany. d.piecha@gmx.de
Weik
Jürgen
J
Kheil
Heike
H
Becher
Gabriele
G
Timmermann
Andreas
A
Jaworski
Andreas
A
Burger
Maren
M
Hofmann
Michael W
MW
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
D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D053509:Matrix Metalloproteinase 13