Endometriosis is a
gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating
abdominal pain and
infertility. Current treatments alleviate moderate
pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth.
Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that
cysteine cathepsins, a group of powerful extracellular matrix
proteases, facilitate endometrial tissue invasion and
endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease
endometriosis lesion implantation. To test this, we used an immunocompetent
endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active
cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with
cathepsins L and K specifically implicated. Human
endometriosis lesions also exhibited greater
cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting
cathepsin activity could block
endometriosis lesion attachment and implantation in vivo.
Intraperitoneal injection of the broad
cysteine cathepsin inhibitor,
E-64, significantly reduced the number of attached
endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that
cathepsin proteases contribute to
endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal
therapy for
endometriosis.