Aug. 17, 2004 Cell biologists of the University of Bonn, in cooperation with the University of Leeds (U.K.) and industry may have discovered a new effective therapy for psoriasis: a specific group of what are known as metalloproteinase inhibitors can normalise the increased tendency of epidermis cells (keratinocytes) to divide, which is the cause of this unpleasant lepidosis. The researchers were not able to detect any toxic side-effects, at least not in cell cultures. Their findings are now being published in the Journal of Investigative Dermatology (Vol. 123, No. 3).
About two million Germans suffer from psoriasis (from the Greek psora meaning 'itching, scratching'). In this incurable disease the regeneration of the epidermis is speeded up enormously: whereas it normally renews itself in just under four weeks, this period is cut to four to seven days in psoriasis patients. The reason is the greatly increased rate of cell division of the keratinocytes. They form a layer which separates the epidermis from the dermis, which lies beneath it. The ageing cells pass from this germinal layer to the surface until they finally scale off.
The disease progresses in waves. Its typical features are clearly defined red areas which are covered with silvery white scales. In the Middle Ages they were thought to be the symptoms of leprosy; a large number of the 'lepers' who were persecuted and even burnt were probably suffering from psoriasis, which is not contagious. What is worse than the changes to the skin itself is the stigma attached to the disease: 'During one of the periods when the disease is more intense many patients think that it is unreasonable to expect people to put up with their presence,' the Bonn cytobiologist Professor Volker Herzog explains. 'Some patients withdraw completely; depressions are not infrequent.'
No toxic side-effects
One of the substances which stimulate the division of the keratinocytes is the protein sAPPá. It is produced during the decomposition of a larger protein, APP. The keratinocytes produce an enzyme which cuts the APP down to size as sAPPá: this is known as the á-secretase. Professor Herzog's research team has now blocked these 'molecular scissors'. 'We knew that certain metalloproteinase inhibitors impede the á-secretase. After adding these substances we observed that the discharge of sAPPá was almost completely arrested in the cells of psoriasis patients. As a result, after adding them the greatly increased division rate of the keratinocytes dropped back to normal values by 50 to 60 per cent,' Christina Siemes, a member of Professor Herzog's team, explains. 'We have been able to confirm this in skin specimens of five psoriasis patients.'
The inhibiting effect of the metalloproteinase inhibitors largely wore off within 72 hours. Moreover, even with fivefold concentration of the active ingredient the research team could not detect any toxic side-effects. For example, among other aspects the number of skin cells which entered into apoptosis remained constant - apoptosis is the cells' 'suicide' programme, which enables them to self-destruct when they are malfunctioning. The cellular protein synthesis was also unaffected.
'Treatment using the metalloproteinase inhibitors which we have been investigating seems to be a new and very promising therapeutic option for psoriasis,' Professor Herzog therefore believes. 'This won't be a magic solution to all our problems, of course - after all, every skin reacts differently.' Furthermore, the substances only alleviate the symptoms. They do not remove the root of the evil, viz. the chronic inflammation of the skin caused by constant attacks by the body's own immune system, to which the keratinocytes react with feverish activity in the cell division field.
The researchers now intend to test their method on animals, using naked mice on which they have transplanted the skin tissue of psoriasis patients. They want to apply the active ingredients locally as an ointment. In addition, the first tests on human beings are planned for the immediate future.
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