Involvement of Cathepsins in Osteoporosis and Allergy and Cathepsin Inhibitors as the New Therapeutic Drugs

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Many hormones and local factors have been reported to be involved in the regulation of bone resorption. However, their mechanisms have remained unclear. This study focused on lysosomal cysteine proteinases and their inhibitors that are thought to play roles in bone collagenolysis.Osteoporotic rats were prepared by feeding a ca-deficient diet. These rats show a decrease in the weight of their femur and increase in the level of hydroxyproline (Hyp) in blood. Furthermore, the activities of cathepsin B and L show a slight invrease in their femur extract, whereas the activity of cathepsin H remained unchanged. Administration of inhibitor of cathepsin, such as E-64a or cystatin to osteoporotic rats caused a dramatic decrease in the activities of cathepsin B, H and L in extract of the femur. Administration of these proteinase inhibitors also reduced the ca- and Hyp-level in blood and do not affect the activity of collagenase. On the other hand, we searched for selective inhibitors of lysosomal cysteine proteinases and discovered a new selective inhibitor (CA-074, derivative of E-64) of cathepsin B in vivo. Administration of CA-074 caused the specific inhibition of cathepsin B in fumer, while H and L activities were not inhibited. However, this specific inhibitor boes not affect the Ca- and Hyp=level in bolld. There results suggest that Cathepsin B may not be involved in collagenolysis. Therefore, cathepsin L might be implicated in degradation of the collagen fibers of bone matric because the collagen is quite susceptible to cathepsin L. The selective inhibitor (s) of cathepsin L might be used for osteoporosis as therapeutic drugs.