Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases.
The tissue inhibitors of matrix metalloproteinases (MMPs), TIMP-1 and TIMP-2, are also angiogenesis inhibitors. Cathepsin B and MMPs are found at sites of neovascularization in pathologies such as cancer and osteoarthritis. Treatment of TIMP-1, TIMP-2, and of a mixture of both inhibitors from human articular chondrocytes with cathepsin B resulted in their fragmentation, whereby they lost their MMP-inhibitory and anti-angiogenic activities. Our data suggest that, besides directly participating in tissue destruction, cathepsin B can be harmful for two further reasons: it raises the activity of the MMPs also in the absence of mechanisms up-regulating these enzymes, and it stimulates angiogenesis. This is a prerequisite for blood vessel invasion in a variety of pathological situations of which cancer and osteoarthritis are prominent examples.
Kostoulas
G
G
University Hospital, Department of Rheumatology, Zurich, Switzerland.
Lang
A
A
Nagase
H
H
Baici
A
A
D002358:Cartilage, Articular / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D002401:Cathepsin B / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors*
D017077:Culture Media, Conditioned; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D002401:Cathepsin B