Cathepsin K (Ctsk), a cysteine protease, is well-known for its strong activity in degrading the extracellular matrix. It is closely related to osteoclast-mediated bone destruction and plays a role in bone resorption [3]. Mutations in the Ctsk gene have been linked to pycnodysostosis, a rare autosomal recessive skeletal dysplasia [5,6,7,8,9].

In a mouse model where Trp53 and Rb1 were ablated in Ctsk-expressing cells (Ctsk-Cre;Trp53f/f/Rb1f/f mice), the animals spontaneously developed osteosarcoma with age, and loss of Trp53/Rb1 in these cells promoted the expression and nuclear translocation of YAP/TAZ. Verteporfin, an inhibitor of YAP/TAZ signaling, delayed osteosarcoma progression in these mice [2]. In another mouse FeCl3 model, Ctsk deficiency prevented stress-related thrombosis, as Ctsk seemed to contribute to thrombosis possibly via modulating vascular inflammation, oxidative production, and apoptosis [4]. In castration-resistant prostate cancer (CRPC), Ctsk was significantly up-regulated, and it regulated tumor growth and metastasis through the IL-17/CTSK/EMT axis and mediated M2 macrophage polarization [1].

In summary, Ctsk is crucial for extracellular matrix degradation and bone resorption. Gene-modified mouse models, such as Ctsk-Cre;Trp53f/f/Rb1f/f and Ctsk-deficient mice, have revealed its roles in osteosarcoma development, stress-related thrombosis, and CRPC, providing potential therapeutic targets for these diseases.

References:

1. Wu, Ning, Wang, YouZhi, Wang, KeKe, Liang, JiaMing, Jiang, Ning. 2022. Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer. In Cell death & disease, 13, 813. doi:10.1038/s41419-022-05215-8. https://pubmed.ncbi.nlm.nih.gov/36138018/

2. Li, Yang, Yang, Shuting, Yang, Shuying. 2022. Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway. In Cells, 11, . doi:10.3390/cells11081361. https://pubmed.ncbi.nlm.nih.gov/35456040/

3. Gao, Li-Hong, Li, Shan-Shan, Yue, Hua, Zhang, Zhen-Lin. 2020. Associations of Serum Cathepsin K and Polymorphisms in CTSK Gene With Bone Mineral Density and Bone Metabolism Markers in Postmenopausal Chinese Women. In Frontiers in endocrinology, 11, 48. doi:10.3389/fendo.2020.00048. https://pubmed.ncbi.nlm.nih.gov/32117071/

4. Jin, Xueying, Yue, Xueling, Huang, Zhe, Kuzuya, Masafumi, Cheng, Xian Wu. 2024. Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model. In Cellular and molecular life sciences : CMLS, 81, 205. doi:10.1007/s00018-024-05240-0. https://pubmed.ncbi.nlm.nih.gov/38703204/

5. Markova, Tatiana Vladimirovna, Kenis, Vladimir, Melchenko, Evgeniy, Nagornova, Tatiana, Dadali, Elena Leonidovna. 2022. Clinical and genetic characterization of three Russian patients with pycnodysostosis due to pathogenic variants in the CTSK gene. In Molecular genetics & genomic medicine, 10, e1904. doi:10.1002/mgg3.1904. https://pubmed.ncbi.nlm.nih.gov/35315254/

6. Huang, Xianglan, Qi, Xuan, Li, Mei, Hu, Ying Ying, Xia, Weibo. 2015. A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin. In Calcified tissue international, 96, 373-8. doi:10.1007/s00223-015-9963-y. https://pubmed.ncbi.nlm.nih.gov/25725806/

7. Sait, Haseena, Srivastava, Priyanka, Gupta, Neerja, Pabbati, Jayalakshmi, Phadke, Shubha R. 2021. Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis. In European journal of medical genetics, 64, 104235. doi:10.1016/j.ejmg.2021.104235. https://pubmed.ncbi.nlm.nih.gov/33945887/

8. Xue, Y, Wang, L, Xia, D, Mao, T, Duan, X. 2015. Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations. In Journal of dental research, 94, 674-81. doi:10.1177/0022034515573964. https://pubmed.ncbi.nlm.nih.gov/25731711/

9. Naeem, Muhammad, Sheikh, Sabeen, Ahmad, Wasim. 2009. A mutation in CTSK gene in an autosomal recessive pycnodysostosis family of Pakistani origin. In BMC medical genetics, 10, 76. doi:10.1186/1471-2350-10-76. https://pubmed.ncbi.nlm.nih.gov/19674475/