The Vitamin D Receptor Is a Wnt Effector that Controls Hair Follicle Differentiation and Specifies Tumor Type in Adult Epidermis

We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by β-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for β-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergises with β-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear β-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high β-catenin and low VDR levels. In mice, EB1089 prevents β-catenin induced trichofolliculomas, while in the absence of VDR β-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling

Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents

Background - Although effective coverage of challenging coronary lesions has warranted the use of overlapping drug-eluting stents, the histopathological response to stent overlap is unknown. Methods and Results - The arterial reaction to overlapping Cypher or Taxus drug-eluting stents was examined in rabbits with bare metal stents, BxVelocity or Express, serving as controls. Single iliac artery balloon injury was followed by placement of 2 overlapping 3.0-mm-diameter drug-eluting stents or bare metal stents in 60 animals ( mean length of overlap, 9.8 +/- 3.6 mm). Stented arteries were harvested at 28 and 90 days for histology. Overlapped segments exhibited delayed healing compared with proximal and distal nonoverlapping sites at 28 days. Overlapped segments in Taxus stents induced significantly more luminal heterophils/eosinophils and fibrin deposition than Cypher; peristrut giant cell infiltration, however, was more frequent in the latter. Overlapping bare metal stents also showed mild delayed healing compared with nonoverlapped segments, but not to the same extent as drug-eluting stents. Although neointimal thickness within the overlap was similar in 28- and 90-day Cypher stents, there was a significant increase with Taxus (P = 0.03). Conclusions - Compared with bare metal stents, drug-eluting stents further delay arterial healing and promote inflammation at sites of overlap. Taxus stents induced greater fibrin deposition, medial cell loss, heterophils/eosinophils, and late neointimal hyperplasia. Patients receiving overlapping drug-eluting stents need more frequent follow-up than patients with nonoverlapping stents

Endothelial Cell Recovery Between Comparator Polymer-Based Drug-Eluting Stents

ObjectivesThe purpose of this study was to assess trends in endothelial coverage and recovery among leading polymer-based drug-eluting stents (DES).BackgroundAutopsy studies of human U.S. Food and Drug Administration (FDA)–approved DES implanted coronary arteries suggest that complications of late stent thrombosis are associated with incomplete endothelial coverage of struts.MethodsRabbits received sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), zotarolimus-eluting stents (ZES), and everolimus-eluting stents (EES) for 14 or 28 days along with MULTI-LINK (ML) Vision control stents. Endothelial coverage above and between struts was measured by morphometric analysis of images acquired through en face scanning electron microscopy. Dual fluorescent immunolabeling was performed for platelet-endothelial cell adhesion molecule (PECAM)-1 and thrombomodulin (TM), factors involved in cell-to-cell contact and thrombogenicity, respectively. In a separate analysis, the endothelial mitogen, vascular endothelial growth factor (VEGF), was also assessed.ResultsVarying rates of endothelialization among comparator DES were most notable at 14 days, where coverage above struts remained poor in SES, PES, and ZES (≤30%) relative to EES and ML Vision controls (≥70%), whereas no significant differences were observed at 28 days. Select DES with poor endothelialization showed a further reduced expression of PECAM-1. All DES showed an absence or weak expression of the antithrombotic cofactor TM. Incomplete endothelialization in select DES was further associated with increased VEGF secretion and messenger ribonucleic acid levels at 14 days, providing evidence of a transitional healing surface.ConclusionsThe present study marks the first comparator analysis of endothelial coverage in leading polymeric DES, supporting disparities in arterial healing based on endothelial regrowth and recovery, favoring newer designs over the current generation of FDA-approved stents

Vitamin D receptor is essential for normal keratinocyte stem cell function

The major physiological role of the vitamin D receptor (VDR) is the maintenance of mineral ion homeostasis. Mutation of the VDR, in humans and mice, results in alopecia. Unlike the effects of the VDR on mineral ion homeostasis, the actions of the VDR that prevent alopecia are ligand-independent. Although absence of the VDR does not prevent the development of a keratinocyte stem cell niche in the bulge region of the hair follicle, it results in an inability of these stem cells to regenerate the lower portion of the hair follicle in vivo and impairs keratinocyte stem cell colony formation in vitro. VDR ablation is associated with a gradual decrease in keratinocyte stem cells, accompanied by an increase in sebaceous activity, a phenotype analogous to that seen with impaired canonical Wnt signaling. Transient gene expression assays demonstrate that the cooperative transcriptional effects of β-catenin and Lef1 are abolished in keratinocytes isolated from VDR-null mice, revealing a role for the unliganded VDR in canonical Wnt signaling. Thus, absence of the VDR impairs canonical Wnt signaling in keratinocytes and leads to the development of alopecia due to a defect in keratinocyte stem cells