Long-term Expression of Cathepsin K Induces Unexpected Proteolytic Feedback to Maintain Proteostasis


Cysteine cathepsins are proteolytic enzymes that have increased production and activity by cells intissue destructive diseases such as atherosclerosis, cancer, and osteoporosis, where they play integral roles indegrading extracellular matrix proteins. Pharmaceutical companies have recognized them as important targets andhave been developing inhibitors, however, all but one of the 16 drugs have been discontinued from clinical trials,mostly due to side effects. There is a need to understand why these well-designed inhibitors have not beendeployable in vivo. Our lab’s previous research has demonstrated that some cathepsins will preferentially degradeother cathepsins, even in the presence of target substrate, a behavior we termed cathepsin cannibalism. CathepsinS (catS), for example, is known to degrade catK over collagen and is hypothesized to also degrade catL.Determining cathepsin cannibalism directionality and substrate preferences will begin to unravel the complexproteolytic network dynamics of these enzymes, and provide insight into their levels in vivo that complicatepharmaceutical dosing and inhibition strategies. These studies may also help elucidate cellular feedback responsesto produce other proteases that can interact and change the amount present in complicated networks. I hypothesizethat stable expression of catK to mimic diseased cells will induce co-regulation of other proteases.

Biomedical Engineering Society Annual Meeting

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