Dkk2, or Dickkopf associated protein 2, is known as an inhibitor of canonical Wnt/β -catenin signaling. The Wnt/β -catenin signaling pathway is crucial for the maintenance of muscle and bone, and Dkk2 thus plays an important role in various biological processes related to this pathway [2,6]. It has also been associated with tumor-related processes, making it significant in cancer research. Genetic models, such as KO/CKO mouse models, are valuable for studying Dkk2's functions.

In androgen-deficient mice with orchidectomy (ORX), Dkk2 mRNA levels were significantly enhanced in soleus muscles, and serum Dkk2 levels increased. Serum Dkk2 levels were negatively related to trabecular bone mineral density at the tibias, suggesting Dkk2 might be involved in androgen-deficiency-induced muscle wasting and osteopenia as a myokine linking muscle to bone [2]. In mechanically unloaded mice, hindlimb unloading (HU) increased Dkk2 expression in soleus muscle and serum Dkk2 levels, while hypergravity decreased them. Serum Dkk2 levels were negatively related to trabecular bone mineral density and positively related to mRNA levels of receptor activator of nuclear factor-kappa B ligand (RANKL) in the tibia. Dkk2 also suppressed osteogenic genes and increased RANKL mRNA levels in mouse osteoblasts, indicating its contribution to disuse-and microgravity-induced bone and muscle loss [6].

In cancer research, DKK2 promotes the progression of oral squamous cell carcinoma (OSCC) through the PI3K/AKT signaling pathway. Its expression is elevated in OSCC tissues compared to normal tissues, and hypoxic conditions can enhance its expression. DKK2 overexpression promotes cell proliferation, migration, and invasion of OSCC, while knockdown inhibits these processes [1]. In colorectal cancer, DKK2 promotes tumor metastasis and angiogenesis through a VEGF-independent but energy-metabolism-related pathway. It accelerates aerobic glycolysis of CRC cells, leading to lactate production which stimulates angiogenesis. Blockade of DKK2 can impede tumor progression, activate tumor-infiltrating CD8+ T cells, and enhance anti-angiogenic therapy in a mouse genetic CRC model with APC and KRAS mutations [3,4]. In pancreatic ductal adenocarcinoma, elevated DKK2 expression predicts poorer prognosis, correlates with cell migration and epithelial-mesenchymal transition, and impairs tumor immunity infiltration [5].

In conclusion, Dkk2 is an important regulator in muscle-bone interactions and is involved in various disease conditions, especially cancer. Studies using KO/CKO mouse models have been instrumental in revealing its role in androgen-deficiency-related muscle and bone changes, as well as in cancer progression, metastasis, and angiogenesis. Understanding Dkk2's functions provides insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Guo, Wenbo, Qu, Yun, Yu, Yang, Hu, Tenglong, Zhou, Shan. 2024. DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway. In Aging, 16, 9204-9215. doi:10.18632/aging.205864. https://pubmed.ncbi.nlm.nih.gov/38795388/

2. Iemura, Shunki, Kawao, Naoyuki, Akagi, Masao, Kaji, Hiroshi. 2020. Role of Dkk2 in the Muscle/bone Interaction of Androgen-Deficient Mice. In Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association, 129, 770-775. doi:10.1055/a-1331-7021. https://pubmed.ncbi.nlm.nih.gov/33352594/

3. Deng, Fengliu, Zhou, Rui, Lin, Chuang, Pan, Mingxin, Zhao, Liang. 2019. Tumor-secreted dickkopf2 accelerates aerobic glycolysis and promotes angiogenesis in colorectal cancer. In Theranostics, 9, 1001-1014. doi:10.7150/thno.30056. https://pubmed.ncbi.nlm.nih.gov/30867812/

4. Hu, Jiajia, Wang, Zhengting, Chen, Zhengxi, Wu, Dianqing, Xiao, Qian. 2020. DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 127, 110229. doi:10.1016/j.biopha.2020.110229. https://pubmed.ncbi.nlm.nih.gov/32559853/

5. Yang, Jianyu, Jiang, Yongsheng, He, Ruizhe, Zhang, Zhigang, Sun, Yongwei. 2019. DKK2 Impairs Tumor Immunity Infiltration and Correlates with Poor Prognosis in Pancreatic Ductal Adenocarcinoma. In Journal of immunology research, 2019, 8656282. doi:10.1155/2019/8656282. https://pubmed.ncbi.nlm.nih.gov/31583260/

6. Kawao, Naoyuki, Morita, Hironobu, Iemura, Shunki, Ishida, Masayoshi, Kaji, Hiroshi. 2020. Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice. In International journal of molecular sciences, 21, . doi:10.3390/ijms21072547. https://pubmed.ncbi.nlm.nih.gov/32268570/