Dkk3, belonging to the DKK family, codes for an evolutionarily conserved secreted glycoprotein. It has two distinct cysteine-rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway [2,5]. Dkk3 is involved in multiple biological processes, and its dysregulation is associated with various diseases, making it a potential biomarker and therapeutic target.

In muscle-related studies, myofiber-specific ablation of Baf60c in mice leads to a robust upregulation of Dkk3, which inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade promotes muscle regeneration, suggesting that Baf60c in myofiber controls muscle regeneration through Dkk3-mediated paracrine signaling [1]. In the context of renal fibrosis, knockdown of Dkk3 in H2O2-treated HK-2 cells and ureteric obstruction (UUO) mice inhibits oxidative stress, maintains mitochondrial homeostasis, and alleviates kidney damage and fibrosis. Upregulation of Dkk3 caused by m6A modification activates the Wnt/β-catenin pathway, leading to mitochondrial dysfunction and promoting renal fibrosis progression [3]. In chronic obstructive pulmonary disease (COPD)-related sarcopenia, Dkk3 is overexpressed in cigarette-smoking-induced muscle atrophy and in patients with COPD. Inhibition of Dkk3 by genetic ablation prevents cigarette-smoking-induced skeletal muscle dysfunction, indicating that Dkk3 could be a potential target for the diagnosis and treatment of sarcopenia in COPD patients [4].

In summary, Dkk3 is a crucial regulator in multiple biological processes. Gene-knockout (KO) or conditional-knockout (CKO) mouse models have revealed its roles in muscle regeneration, renal fibrosis, and COPD-related sarcopenia. These findings suggest that Dkk3 could be a promising target for treating related diseases [1,3,4].

References:

1. Xu, Jingya, Li, Xiaofei, Chen, Wei, Shan, Pengfei, Meng, Zhuo-Xian. 2023. Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling. In The Journal of experimental medicine, 220, . doi:10.1084/jem.20221123. https://pubmed.ncbi.nlm.nih.gov/37284884/

2. Katase, Naoki, Nagano, Kenichi, Fujita, Shuichi. 2020. DKK3 expression and function in head and neck squamous cell carcinoma and other cancers. In Journal of oral biosciences, 62, 9-15. doi:10.1016/j.job.2020.01.008. https://pubmed.ncbi.nlm.nih.gov/32032750/

3. Song, Jianling, Chen, Yanxia, Chen, Yan, Ke, Ben, Fang, Xiangdong. 2024. DKK3 promotes renal fibrosis by increasing MFF-mediated mitochondrial dysfunction in Wnt/β-catenin pathway-dependent manner. In Renal failure, 46, 2343817. doi:10.1080/0886022X.2024.2343817. https://pubmed.ncbi.nlm.nih.gov/38682264/

4. Wang, Zilin, Deng, Mingming, Xu, Weidong, Zhou, Xiaoming, Hou, Gang. 2024. DKK3 as a diagnostic marker and potential therapeutic target for sarcopenia in chronic obstructive pulmonary disease. In Redox biology, 78, 103434. doi:10.1016/j.redox.2024.103434. https://pubmed.ncbi.nlm.nih.gov/39571512/

5. Hamzehzadeh, Leila, Caraglia, Michele, Atkin, Stephen L, Sahebkar, Amirhossein. 2018. Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers? In Journal of cellular physiology, 233, 4595-4605. doi:10.1002/jcp.26313. https://pubmed.ncbi.nlm.nih.gov/29206297/