Dickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation

The Wnt signaling pathway plays essential roles in tissue or organ homeostasis by regulating cell proliferation and differentiation. Upon tissue or organ injury, inflammation is coupled with tissue repair and regeneration process. The canonical Wnt signaling transduction pathway is crucial for cell proliferation, cell differentiation, and tissue regeneration. Dickkopf1 (DKK1) is a quintessential Wnt antagonist that inhibits the Wnt-mediated tissue repair process. Recent studies reported increased levels of DKK1 in many diseases such as cancer, infection, and musculoskeletal diseases. In many cases, the role of DKK1 has been identified as a pro-inflammatory ligand and the expression levels are associated with poor disease outcomes. A variety of cell types including platelets, endothelial cells, and cancer cells secrete DKK1 upon stimuli. This puts DKK1 in a unique place to view immune responses from multicellular interactions in tissue injury and repair process. In this review, we discuss recent efforts to address the underlying mechanism regarding the pro-inflammatory role of DKK1 in cancer, bone diseases, and other inflammatory diseases.