{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dickkopf‐1 (DKK1) is a potent, secreted antagonist of canonical Wnt signaling that exerts its function by binding to the Wnt coreceptors LRP5/6 and, together with Kremen proteins, promoting receptor internalization and pathway inhibition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Its regulatory action on Wnt signaling is central to multiple biological processes. In bone biology, for example, impaired inhibition of Wnt signaling—as occurs with defective DKK1 function—is associated with high bone mass phenotypes, whereas excessive DKK1 expression (such as that secreted by myeloma cells or induced by inflammatory cytokines like TNF‐α) suppresses osteoblast differentiation and contributes to osteolytic lesions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in bone remodeling, DKK1 is widely utilized as an experimental tool to modulate Wnt activity in diverse organ systems. For instance, adenoviral expression of DKK1 effectively suppresses gastrointestinal epithelial proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and its application in models of liver zonation and tooth development or limb patterning demonstrates that tight regulation of Wnt signaling by DKK1 is essential for proper tissue morphogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of cancer, DKK1 plays diverse roles that are dependent on tumor type and microenvironment. Elevated levels of DKK1 serve as a diagnostic biomarker in hepatocellular carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", whereas in colorectal cancer, hypermethylation-associated silencing of the DKK1 promoter supports a tumor-suppressor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In medulloblastoma, DKK1 expression contributes to molecular subgroup classification, and its autocrine production by latency-competent cancer cells facilitates entry into a slow-cycling, immune-evasive state."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Moreover, DKK1 secreted by mesenchymal stem cells can inhibit tumor cell growth by downregulating β-catenin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, modulation of DKK1 expression by regulatory inputs adds further layers to its biological impact. For example, transforming growth factor-β can decrease DKK1 expression to stimulate Wnt signaling in fibrotic conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and microRNAs such as miR-29a target DKK1 to potentiate osteoblast differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Similarly, inflammatory signals (e.g., interferon-γ) induce DKK1, thereby linking cytokine signaling to the regulation of epithelial apoptosis and proliferative balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight DKK1 as a multifaceted regulator of canonical Wnt signaling whose activity is pivotal for skeletal remodeling, tissue development, and tumorigenesis. Its dynamic modulation—whether through overexpression or suppression—can have profound effects on cell differentiation, proliferation, and survival in both physiologic and pathologic settings.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lynn M Boyden, Junhao Mao, Joseph Belsky, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High bone density due to a mutation in LDL-receptor-related protein 5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa013444"}], "href": "https://doi.org/10.1056/NEJMoa013444"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12015390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12015390"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Bingyu Mao, Wei Wu, Gary Davidson, et al. 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