Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications.

T he diabetic foot syndrome represents a major problem in the health care of diabetic patients. Understanding the molecular basis of this disease is an important step toward a rational treatment. Due to the systemic character of diabetes, disturbances in several basic cell functions appear to contribute to impaired wound healing. Many essential processes of normal wound healing are regulated in large part by growth factors and proteases, and changes of their expression and activity are relevant for the pathogenesis of the chronic wound. This review summarizes the current status of research on diabetic foot syndrome and describes new implications for the treatment of this syndrome. The diabetic foot syndrome is clearly one of the most important complications of diabetes. It not only occurs as a typical complication in the late stages of diabetes but also in patients with newly diagnosed diabetes (1). Despite the postulations of the St. Vincent Declaration that within 5 years the amputation rate has to be reduced by 50%, there are 30,000 amputations reported each year in Germany due to the diabetic foot syndrome (2–6). Greater success in reducing the diabetic foot syndrome can be achieved using structured diagnosis, classification, and therapy of diabetes (7–12). For example, chronically elevated blood glucose levels result in reduced leukocyte function and cell malnutrition, which contribute to a high rate of wound infection and associated healing problems (13,14). Due to the systemic effects of diabetes, not only do cellular abnormalities exist but interactions of growth factors and other mediators of wound healing are also impaired (15,16). Thus, understanding the cellular and molecular abnormalities that contribute to the diabetic foot syndrome will enable the rational development of treatments that will reduce the incidence and severity of this major complication of diabetes.