Jack Janett

Background: Osteosarcoma is a type of malignant bone tumor of osteoid-producing cells that usually affects the long bones in the arms and legs, including the tibia, femur, and humerus. It mainly affects adolescents near their growth plates, so it can impair growth. These aggressive tumors commonly metastasize to the lungs in approximately 20% of patients, and they produce undetectable micro-metastases in 80% of patients by the time of initial diagnosis¹. Osteosarcoma dysregulates the Wnt signaling pathway, which normally drives the differentiation of mesenchymal stem cells to osteoblasts. Osteosarcoma tumors accomplish this by secreting Dickkopf-1 (Dkk-1), which is a canonical Wnt/β-catenin signaling inhibitor. This allows Dkk-1 to dysregulate osteoblast differentiation and bone resorption, disorganize bone repair, and increase stimulation of metastases^2-3. However, there is no consensus in the scientific community how to pharmacologically disrupt this pathway. Researchers are currently investigating various mechanisms to optimally inhibit Dkk-1, to steer away from the dependence on chemotherapy and the burden of osteolytic bone lesions.

Objective: In this narrative review, we explored the novel approaches by which inhibition of Dkk-1 in osteosarcoma microenvironments could prevent tumor metastasis and relapse.

Search Methods: An online search in the Google Scholar database was conducted from 2017 to 2025 using the following keywords: “osteosarcoma”, “Dkk-1”, “Wnt signaling”, “metastasis”, and “therapeutic approaches”.

Results: Studies indicate that there are three main mechanisms to counteract the pathogenic role of Dkk-1. First, Dkk-1 output can be blocked by antisense phosphorodiamidate morpholino oligomer conjugated to a cell-penetrating octa-guanidine dendrimer. This vivo morpholino (DkkMo) reduces Aldh1a1 production, which disrupts stress response and survival pathways and production ^4-5. In addition, there are two small molecule inhibitors of Dkk-1. WAY262611 is a small molecule inhibitor of Dkk-1 that induces nuclear translocation of β-catenin in osteosarcoma cells, which increased β-catenin-driven transcription. WAY262611 was proven to slow the growth of an orthotopically implanted patient-derived xenograft of osteosarcoma and inhibits distant metastasis². XD23 is a small molecule compound that demonstrates broad-spectrum antitumor activity. Flow cytometry analysis conveyed a significant increase in the percentage of osteosarcoma cells in the G0/G1 phase. This elucidates XD23’s capability to pause osteosarcoma cell growth and trigger G0/G1 phase arrest⁶. Lastly, two micoRNA targeting molecules have been shown to downregulate Dkk-1. MicroRNA-107 is located on chromosome 10 and is abnormally expressed in osteosarcoma tumors. Dkk-1 is a target gene of microRNA-107 in osteosarcoma. Dual-luciferase reporter gene assays show that the microRNA-107 binding site is in the 3’UTR region of Dkk-1. qRT-PCR and Western blotting of miR-107, Dkk-1, β-catenin, Bcl-2, c-Myc, casase-3, and PARP showed lower expression levels of Dkk-1 in osteosarcoma tissue⁷. MicroRNA-152 is downregulated in patients with osteosarcoma, which leads to cell proliferation and decreases apoptosis. Overexpression of microRNA-152 also inhibits cell proliferation, induces apoptosis, and promotes caspase-3/9 activity⁸.

Conclusions: Current therapeutic approaches of osteosarcoma still lead to significant pain and immobility, negatively impact a patient’s quality of life, and fail to inhibit metastasis. Dkk-1 disrupts the balance between canonical Wnt and non-canonical Wnt signaling, which prevents osteoblast differentiation, disorganizes bone repair, and increases bone resorption. Targeting Dkk-1 has been shown to restore function to the Wnt/β-catenin signaling pathway. This is a promising adjunct therapy alongside surgery or chemotherapy that warrants further investigation.

Works Cited:

1. Baglio SR, Lagerweij T, Pérez-Lanzón M, et al. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression [published correction appears in Clin Cancer Res. 2018 Feb 1;24(3):724. doi: 10.1158/1078-0432.CCR-17-3198.]. Clin Cancer Res. 2017;23(14):3721-3733. doi:10.1158/1078-0432.CCR-16-2726
2. Tal A, Gunawardana-Zeigler S, Peng D, et al. Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis. Mol Cancer Ther. Published online January 9, 2025. doi:10.1158/1535-7163.MCT-24-0744
3. Goldstein SD, Hayashi M, Albert CM, Jackson KW, Loeb DM. An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis. Clin Exp Metastasis. 2015;32(7):703-715. doi:10.1007/s10585-015-9738-x
4. Haskell A, Pan S, Reese R, et al. Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental osteosarcoma. Sci Rep. 2025;15(1):1878. Published 2025 Jan 13. doi:10.1038/s41598-024-84037-4
5. Pan S, Cesarek M, Godoy C, et al. Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms. Br J Cancer. 2022;127(1):43-55. doi:10.1038/s41416-022-01764-z
6. Xie Q, Shen Y, Yang Y, et al. Identification of XD23 as a potent inhibitor of osteosarcoma via downregulation of DKK1 and activation of the WNT/β-catenin pathway. iScience. 2024;27(9):110758. Published 2024 Aug 20. doi:10.1016/j.isci.2024.110758
7. Zhang ZC, Liu JX, Shao ZW, et al. In vitro effect of microRNA-107 targeting Dkk-1 by regulation of Wnt/β-catenin signaling pathway in osteosarcoma. Medicine (Baltimore). 2017;96(27):e7245. doi:10.1097/MD.0000000000007245
8. Zhao X, Sun S, Xu J, Luo Y, Xin Y, Wang Y. MicroRNA-152 inhibits cell proliferation of osteosarcoma by directly targeting Wnt/β-catenin signaling pathway in a DKK1-dependent manner. Oncol Rep. 2018;40(2):767-774. doi:10.3892/or.2018.6456