title: Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo.
abstract: The secosteroidal hormone 1,25-dihyroxyvitamin D [1,25(OH)(2)D(3)] and its receptor, the vitamin D receptor (VDR), are crucial regulators of epidermal proliferation and differentiation. However, the effects of 1,25(OH)(2)D(3)-directed signaling on oral keratinocyte pathophysiology have not been well studied. We examined the role of 1,25(OH)(2)D(3) in regulating proliferation and differentiation in cultured oral keratinocytes and on the oral epithelium in vivo. Using lentiviral-mediated shRNA to silence VDR, we generated an oral keratinocyte cell line with stable knockdown of VDR expression. VDR knockdown significantly enhanced proliferation and disrupted calcium- and 1,25(OH)(2)D(3)-induced oral keratinocyte differentiation, emphasizing the anti-proliferative and pro-differentiation effects of 1,25(OH)(2)D(3) in oral keratinocytes. Using vitamin D(3)-deficient diets, we induced chronic vitamin D deficiency in mice as evidenced by decreased serum 25-hydroxyvitamin D (25OHD) concentrations. The vitamin D-deficient mice manifested increased proliferation of the tongue epithelium, but did not develop any morphological or histological abnormalities in the oral epithelium, suggesting that vitamin D deficiency alone is insufficient to alter oral epithelial homeostasis and provoke carcinogenesis. Immunohistochemical analyses of human and murine oral squamous cell carcinomas showed increased VDR expression. Overall, our results provide strong support for a crucial role for vitamin D signaling in oral keratinocyte pathophysiology.
authors.affiliation: Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Feng-Ning F
authors.initials: FN
authors.lastname: Yuan
authors.affiliation: University of Connecticut Health Center, School of Dental Medicine, Farmington, CT 06032, USA.
authors.forename: Jayasanker
authors.initials: J
authors.lastname: Valiyaparambil
authors.affiliation: Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Woods
authors.affiliation: Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Huy
authors.initials: H
authors.lastname: Tran
authors.affiliation: University of Connecticut Health Center, School of Dental Medicine, Farmington, CT 06032, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Pant
authors.affiliation: Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Mallya
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000172:deficiency / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004817:Epidermis / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D009055:Mouth / Q000166:cytology*; D009062:Mouth Neoplasms / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014808:Vitamin D Deficiency / Q000473:pathology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; D014815:Vitamins; D002117:Calcitriol