Dickkopf-related Protein 2 Promotes Hair Growth by Upregulating the Wnt/β-catenin Signaling Pathway in Human Dermal Papilla Cells

Background: The Wnt/β-catenin signaling pathway is crucial for the development, initiation, and growth of hair follicles (HFs).The Dickkopf-related protein (DKK) gene family encodes secreted proteins modulating the Wnt/β-catenin signaling pathway.Studies have reported that DKK1 promotes the regression of HFs and serves as a pathogenic mediator in male pattern baldness.However, the role of DKK2 on human hair growth has not yet been explored.Objective: This study investigates direct effect of DKK2 on hair growth using human dermal papilla cell (DPC) cultures and ex vivo human HF organ cultures.Methods: To elucidate the effect of DKK2 on hair growth, we examined the effect of recombinant human DKK2 (rhDKK2) treatment on cell viability, expression of mRNA and protein related to the Wnt/β-catenin signaling pathway, and cell growth in cultured human DPCs.We also performed ex vivo organ culture of HFs with rhDKK2 and measured changes in hair shaft length for 8 days.Results: Treatment with rhDKK2 led to a dose-dependent rise in the proliferation of human DPCs (p<0.05),reaching levels comparable to those induced by 1 μM minoxidil.Moreover, rhDKK2 increased the expression of Wnt/β-catenin target genes, phosphorylated extracellular signal-regulated kinase, and cyclin-D1; it also increased the BAX-to-Bcl-2 ratio and downregulated the bone morphogenetic protein 2 gene.In human HF organ cultures, relative to the control treatment, rhDKK2 treatment significantly increased hair shaft elongation (p<0.01).Conclusion: Our results indicate that rhDKK2 could promote hair growth by facilitating the proliferation of human DPCs through activation of the Wnt/β-catenin signaling pathway.