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    Current therapies for cancer including, chemotherapy, radiotherapy, and surgery, have massive side effects and are immediate/short lived. Cancer Immunotherapy has the potential prospect of generating long-lasting protective tumor immunity. Cathepsin K (Ctsk), which was discovered by our lab and known to modulate both the immune system and bone resorption, is an important target for cancer immunotherapy. Remarkably, knockout of Ctsk in 4T1 breast cancer xenografted mice results in reduction in tumor size, increases in survival time and a decrease in tumor infiltrating macrophages from whole-body cathepsin K knockout. This indicates that the immunomodulatory effects originate from changes in the host, meaning that cathepsin K directed therapy would treat the “healthy” cells, such as endothelial cells and cells of the innate immune system, rather than the cancer cells directly. Our study reveals a role of Cathepsin K in immune tolerance outside of the ‘vicious cycle’ seen in the bone.
    Since adeno-associated virus serotype (AAV) gene therapy has been proven safe, practical, and well-tolerated by humans, and effective in long-term treatment at various doses, we used AAV-mediated RNAi to investigate the effects of Cathepsin K silencing in a mouse models of multiple diseases. Our data further reveals that AAV-shRNA-Cathepsin K (AAV-sh-Ctsk) also protects against cartilage and proteoglycan loss in both the collagenase induced osteoarthritis mouse model and medial meniscus (DMM) mouse model of osteoarthritis. We have also determined that Ctsk deficiency protected mice from bone loss in the spontaneous rheumatoid arthritis human TNF transgenic (hTNF-Tg) mouse model. In the spontaneous rheumatoid arthritis human TNF transgenic (hTNF-Tg) mouse model. Compared to CtsK+/+:TNF-Tg mice, CtsK-/-:TNF-Tg mice were well protected and CtsK+/-:TNF-Tg were partially protected from bone loss. In addition, the arthritis clinical score of immunized CtsK-/- mice with Collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis, was significantly lower than that of wild-type mice with CIA (p<0.001). This indicates that CtsK-/- mice were protected from CIA.
    The critical need for new treatments for osteoclast-related bone diseases such as osteoporosis have been became more urgent by recent reports that the negative effects (e.g., jaw osteonecrosis) of currently used osteoclast inhibitors (bisphosphonate) may outweigh the benefits in some patients. Cathepsin K plays an essential role in osteoclast function and the degradation of protein components of the bone matrix. The human syndrome pycnodysostosis, in which bone resorption is impaired, results from mutations in Cathepsin K. Importantly, in the mouse model of periodontitis, AAV-mediated Cathepsin K knockdown protected mice from P. gingivalis--stimulated bone resorption by more than 80%. AAV-sh-Ctsk also reduced inflammation by reducing the expression of cytokines and T cell numbers in the periodontal lesion.   Similarly, AAV-sh-Ctsk reduced bacterial infection-stimulated bone resorption by 88% and decreased in mononuclear leukocyte infiltration and inflammatory cytokine expression.
    Targeting Ctsk enables the greatly needed reduction in side-effects while increasing efficiency and efficacy in the treatment of various pathological disorders. We are thus extremely excited by the potential clinical benefits of this research approach in targeting several osteoclast-related disorders.