title: Combined Deletion of the Vitamin D Receptor and Calcium-Sensing Receptor Delays Wound Re-epithelialization.
abstract: When the skin is injured, keratinocytes proliferate, migrate, and differentiate to regenerate the epidermis. We recently showed that ablation of the vitamin D receptor (Vdr) in keratinocytes delays wound re-epithelialization in mice also fed a low-calcium diet, implicating a cooperative role of Vdr and calcium signaling in this process. In this study, we examined the role of vitamin D and calcium signaling in wound healing by deleting their receptors, Vdr and the calcium-sensing receptor (Casr). Gene expression profiling of neonatal epidermis lacking both Vdr and Casr [Vdr and Casr double knockout (DKO)] specifically in keratinocytes revealed that DKO affects a number of pathways relevant to wound healing, including Vdr, β-catenin, and adherens junction (AJ) signaling. In adult skin, DKO caused a significant delay in wound closure and re-epithelialization, whereas myofibroblast numbers and matrix deposition were unaffected. The injury-induced proliferation of epidermal keratinocytes was blunted in both epidermis and hair follicles, and expression of β-catenin target genes was reduced in the DKO. Expression of E-cadherin and desmoglein 1 was reduced in the shortened leading edges of the epithelial tongues re-epithelializing the wounds, consistent with the decreased migration rate of DKO keratinocytes in vitro. These results demonstrate that Vdr and Casr are required for β-catenin-regulated cell proliferation and AJ formation essential for re-epithelialization after wounding. We conclude that vitamin D and calcium signaling in keratinocytes are required for a normal regenerative response of the skin to wounding.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94158.|Department of Dermatology, University of California San Francisco, San Francisco, California 94158.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94158.|School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Hu
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, California 94158.
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, California 94158.
authors.forename: Chak
authors.initials: C
authors.lastname: Fong
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, California 94158.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Tu
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, California 94158.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062326:Re-Epithelialization / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014945:Wound Healing / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C577923:CASR protein, mouse; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin