Dickkopf‐1 is involved in dexamethasone‐mediated hair follicle regression

Abstract

The stress-related neurohormones including glucocorticoids (GCs) are secreted by hair follicles (HFs), and GCs suppress murine hair growth in vivo. In this study, we found that dexamethasone (Dex), a synthetic GC, increased the expression of dickkopf-1 (Dkk1), a known catagen inducer, in dermal papilla (DP) cells, but not in follicular keratinocytes. The neutralizing Dkk1 antibody significantly attenuated the Dex-induced inhibition of human hair shaft elongation. In addition, the neutralizing Dkk1 antibody delayed Dex-induced catagen in mice.Collectively, our data strongly suggest that stress-related neurohormones cause DP cells to secrete Dkk1, thereby leading to stressassociated disturbances in hair growth. | BACKGROUNDIncreased secretion of cortisol, the principal glucocorticoid (GC) hormone, is triggered in response to psychosocial stress on the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol is also secreted by human hair follicles (HFs), which act as a functional equivalent of the HPA axis.[1] Dexamethasone (Dex), a synthetic GC, induces catagen, also known as the HF regression phase, in mice. [2,3] upon interaction with GC, the glucocorticoid receptor (GR) translocates into the nucleus, where it mediates a variety of effector mechanisms. [4] A recent study has shown that GR is expressed in human dermal papilla (DP) cells and that Dex inhibits the proliferation of DP cells and decreases the expression of growth factors required for hair growth. [5] These results strongly suggest that stressassociated suppression of hair growth may be due to GC-induced changes in DP cells. Furthermore, we have previously shown that dickkopf-1 (Dkk1) promotes catagen by inducing apoptosis in follicular keratinocytes as well as by suppressing Wnt/β-catenin signalling.[6] | QUESTION ADDRESSEDFirst, we tested whether Dex induced the secretion of Dkk1 from follicular cells. Next, we investigated whether Dkk1 was involved in Dex-mediated HF regression. | EXPERIMENTAL DESIGNExperiments were performed as previously described, [7] and the detailed methods are included in Data S1. | RESULTSWe found that GR is strongly expressed in inner and outer root sheath (ORS) of hair follicles. We also found relatively weak expression of GR in matrix, DP and dermal sheath (n=5; Fig. S1). We observed that DKK1 mRNA is upregulated in DP cells (n=3) in response to Dex as examined by RT-PCR and real-time PCR ( Figure 1A,C). The time-course study showed that DKK1 expression is upregulated in DP cells as early as 6 hours after a 100 nM Dex treatment (Fig. S2). Data from ELISA (n=3) also showed that the concentration of Dkk1 in the DP conditioned medium is increased in response to Dex ( Figure 1E). These results are consistent with those obtained in previous studies that reported an increase in Dkk1 expression in osteoblasts and periodontal ligament stem cells treated with Dex. [8,9] Furthermore, Ru486, a synthetic GR antagonist, significantly attenuated Dex-induced DKK1 mRNA expression in DP cells (n=3; Figure 1F,G), demonstrating that ...

Protective effects of human umbilical cord blood‑derived mesenchymal stem cells against dexamethasone‑induced apoptotic cell death in hair follicles

“…These results suggested that hUcB-MScs may prevent hair catagen by suppressing dKK-1 expression. Although a previous study indicated that dex increased dKK-1 secretion from hdPcs followed by outer root sheath apoptosis, this did not confirm that Dex directly influences keratinocyte cell death (37). The results of the present study demonstrated that dex inhibited cell proliferation, followed by the induction of keratinocyte apoptosis.…”

“…Topical administration of dex causes hair follicle degeneration, thus indicating the clinical phenotype of the catagen phase (36). In addition, dex application increased dKK-1 protein expression levels in human dermal papilla cells, which was followed by hair follicle apoptosis (37). dKK-1 acts as an antagonist of the Wnt/β-catenin pathway, and secretory dKK-1 induces apoptosis of follicular keratinocytes (38).…”

Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles

“…This boost in Wnt signalling enhances human hair shaft formation and inhibits catagen entry. Therefore, Dickkopf-related protein 1 (DKK1) is not the only important regulator of Wnt activity in the human HF [ 34 ], and SFRP1 is a viable alternative target molecule for the therapeutic up-regulation of hair growth–promoting Wnt signalling.…”

Skin transcriptome reveals the dynamic changes in the Wnt pathway during integument morphogenesis of chick embryos

“…DKK1 and NKD1 are antagonistic inhibitors of the canonical Wnt signaling pathway [ 42 , 43 ]. DKK1 also has an inhibitory effect on the differentiation of mesenchymal stem cells to fibroblasts [ 44 – 46 ].…”