Jordan Myers

Background: Osteolytic bone lesions are seen in a majority of patients with various forms of bone cancer and bone metastasis, with over 65% of Multiple Myeloma (MM) patients having pathologic fractures secondary to osteolytic bone lesions at some point in the course of their disease.¹ Osteolytic bone lesions are bone defects seen when normal bone remodeling homeostasis is disrupted, usually with a pathophysiologic cause. Malignant osteolytic lesions are a common sequela often acquired due to cancers and metastatic processes. DKK1 has been identified as a target for development of novel chemotherapeutics/pharmaceutical developments. DKK1 is an inhibitor of Wnt signaling, which is associated with regulation of osteoclast bone resorption.

Research objective: The purpose of this study is to analyze the current literature and understanding of the role of Dkk1 in the development of osteolytic bone lesions, as well as to identify target areas for future studies.

Search Methods: A broad search was conducted utilizing PubMed’s search feature. The key words “Dkk1 osteolytic lesions,” “osteolytic bone disease” and “malignant bone disease mechanism” were used to identify potential publications of interest and relevance, searches were narrowed down using a filter for manuscripts published from 2017-present.

Results: Studies indicate that DKK1 expression is increased in patients with MM. This increase is even more significant in MM patients with osteolytic lesions, demonstrating that there is a causal relationship between DKK1 and bone catabolism. Further studies were conducted to assess for the role of DKK1 and bone catabolism amongst other cancer lines. Upregulated DKK1 expression was positively associated with osteolytic lesions in MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). Pharmacologic targets have been developed to regulate DKK1. In a study on mice injected with MM culture cells, DKK1 antagonists were found to prevent loss of bone and contributed to increased bone strength in these mice. This was found to be secondary to decreased osteoblast activity. To develop a proper chemotherapeutic agent, a study utilized an antisense morpholino to block DKK1 in an osteosarcoma mouse model. DKK1 results in accelerated tumor growth and bone catabolism as demonstrated by previous studies, but this study found that DKK1 that was blocked with the morpholino demonstrated that inhibition of DKK1 inhibits tumor expansion both in vitro and in vivo. Morpholino also induces tumor necrosis in vivo andDKK1 blockade also disrupted stress response and cell survival pathways. This shows that pharmacologic inhibition of DKK1 is an effective pharmacologic strategy across multiple models of cancer, making a viable option for targeting metastatic osteolytic lesions associated with other primary cancers, such as prostate or breast cancer.

Conclusion: DKK1 contributes to pathologic fractures and osteolytic bone lesions. Inhibition of DKK1 via its different regulatory molecules results in decreased bone resorption and tumorigenesis. Current pharmacologic therapies manage to suppress activity of DKK1, but these have significant side effects and can be caustic to several organ systems within these patients. Future studies should continue to develop potential chemotherapeutics/pharmacologic drugs to target DKK1 for use in different cancer lines and/or suppression of bone resorption from metastasis.

Works Cited

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2. Yue Z, Niu X, Yuan Z, et al. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J Clin Invest. 2022;132(2):e144579. doi:10.1172/JCI144579
3. Simic MK, Mohanty ST, Xiao Y, et al. Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma. J Bone Miner Res. 2023;38(6):814-828. doi:10.1002/jbmr.4809
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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
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