Dihydrotestosterone-Inducible Dickkopf 1 from Balding Dermal Papilla Cells Causes Apoptosis in Follicular Keratinocytes

Abstract

Recent studies suggest that androgen-driven alteration to the autocrine and paracrine factors produced by scalp dermal papilla (DP) cells may be a key to androgen-potentiated balding. Here, we screened dihydrotestosterone (DHT)-regulated genes in balding DP cells and found that dickkopf 1 (DKK-1) is one of the most upregulated genes. DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT. A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells. Analysis of co-cultured ORS cells showed a significant increment of sub-G1 apoptotic cells in response to DHT. Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death. In addition, DHT-induced epithelial cell death in cultured hair follicles was reversed by neutralizing DKK-1 antibody. Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia. Altogether, our data strongly suggest that DHT-inducible DKK-1 is involved in DHT-driven balding.

Visible-to-Near IR Quantum Dot–Based Hypermulticolor High-Content Screening of Herbal Medicines for the Efficacy Monitoring of Hair Growth Promotion and Hair Loss Inhibition

“…Therefore, the growth of ORS cells is inhibited by DKK-1, and balding dermal papilla cells (DPC) are activated. Kwack et al 22 demonstrated that 50-100 nM DHT increased the expression level of DKK-1 mRNA in 3 to 6 h in HFDPC. The upregulation of DKK-1 induced by DHT in DPC induced apoptotic cell death.…”

Dickkopf-1 Promotes Hyperglycemia–Induced Accumulation of Mesangial Matrix and Renal Dysfunction

“…13,15 DKK1 reportedly induces apoptosis of various cell types. 43,44 HG impairs Wnt/␤-catenin-dependent survival of mesangial cells. 20 We speculate that DKK1 may be a potent Wnt inhibitor that promotes apoptosis of mesangial cells induced by HG.…”

Biology of Human Hair: Know Your Hair to Control It

“…In this model, androgens act directly on DP cells where they bind to androgen receptors and then initiate altered gene expression of regulatory factors modulating indirectly the period of time when hair is growing, size and activity of the DP, keratinocytes and melanocytes. The factors produced by these populations may be soluble paracrine factors and/or extracellular matrix factors, including insulin-like growth factor-1 (IGF-1) in growth stimulation [105], stem cell factor in altered pigmentation [102] and transforming growth factor-b [106,107] and dickkopf 1 [108] in inhibition. The opposite effects of androgens on beard and scalp follicles probably reflect differences in androgen receptor content, which is higher in beard DP than in occipital hair DP [109] and/or 5a-reductase activity, which is higher in beard than in scalp [110].…”