Expression of Matrix-Metalloproteinases and their Inhibitors in Human Cholesteatomas

Abstract

The proteolytic erosion of the temporal bone is the key event in the pathognomonic course of cholesteatoma progression. the molecular mechanisms of bone resorption, endangering the ossicles, the inner ear, the facial nerve, large vessels or the brain, are not understood. Recently, a new family of proteolytic enzymes, the matrix-metalloproteinases (MMP's) has been described and identified, which seems to play a pivotal role in matrix- and bone homeostasis and inflammatory osteolytic diseases, e.g. osteoarthritis and periodontitis. These enzymes are sophisticatedly controlled by specific inhibitors and activation cascades. We investigated whether human cholesteatoma tissue expresses MMP's and MMP-inhibitors. by immunocytochemistry of cholesteatoma-cryosections, the expression of MMP-2 (72 kD collagenase), MMP-9 (92 kD collagenase), and MMP-3 (stromelysin-1) could be seen to be strictly confined to the basal and suprabasal cell layer of the cholesteatoma epithelium. the neutrophil collagenase (MMP-8) showed a more disseminated expression in the epithelium and the granulation tissue as well. the tissue inhibitor of metalloproteases, TIMP-I, could be detected only in very limited areas of the granulation tissue in a quite randomized manner. Therefore, a derailment in favor of proteolysis of the normally tightly controlled MMP-system might be postulated. the results indicate that members of the MMP-family could play an active role in the molecular mechanisms of cholesteatoma invasion into the temporal bone. This offers new insights into the pathophysiology of the disease and of potential therapeutic approaches.

Key Words:

• MMP
• collagenase
• middle ear
• cholesteatoma
• immunocytochemistry
• bone resorption