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Increased integrity of cell–cell junctions accompanied by increased expression of claudin 4 in keratinocytes stimulated with vitamin D3

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Abstract

The stratified squamous epithelium has a multilayer structure formed by the differentiation of the keratinized epithelium, which covers the skin and oral mucosa. The epithelium plays a central role in regulating the interactions between the immune system and pathogens. The tight junction (TJ) barrier, which is composed of adhesion molecules called claudins (CLDN), is critical for the homeostasis of the skin and oral mucosa. Furthermore, the crucial roles of vitamin D3 (VD3) in the pathogeneses of skin and oral mucosal disease have been suggested. The aim of this in vitro study was to observe the correlations between the integrity of the keratinocyte population and the expression levels of CLDN1 and CLDN4 in gingival epithelial cells, stimulated with VD3. CLDN 1 and 4 expression levels were down and upregulated, respectively, in the cells stimulated with VD3. Additionally, transepithelial electrical resistance (TEER) levels were increased in the stimulated cells when compared to the controls. These findings indicate that CLDN 4 may play a more important role in the TJ barrier than CLDN 1. Hence, the therapeutic effect of VD3 in skin and oral diseases may be regulated by the increase in the expression of CLDN 4.

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References

  1. Sandjeu Y, Haftek M (2009) Desmosealin and other components of the epidermal extracellular matrix. J Physiol Pharmacol 60(Suppl 4):23–30

    PubMed  Google Scholar 

  2. Yoshida C, Takeichi M (1982) Teratocarcinoma cell adhesion: identification of a cell-surface protein involved in calcium-dependent cell aggregation. Cell 28:217–224

    Article  CAS  PubMed  Google Scholar 

  3. Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7:619–627

    Article  CAS  PubMed  Google Scholar 

  4. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ban Y, Dota A, Cooper LJ, Fullwood NJ, Nakamura T, Tsuzuki M, Mochida C, Kinoshita S (2003) Tight junction-related protein expression and distribution in human corneal epithelium. Exp Eye Res 76:663–669

    Article  CAS  PubMed  Google Scholar 

  6. Leyvraz C, Charles RP, Rubera I, Guitard M, Rotman S, Breiden B, Sandhoff K, Hummler E (2005) The epidermal barrier function is dependent on the serine protease CAP1/Prss8. J Cell Biol 170:487–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li J, Ananthapanyasut W, Yu AS (2011) Claudins in renal physiology and disease. Pediatr Nephrol 26:2133–2142

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nielsen HL, Nielsen H, Ejlertsen T, Engberg J, Günzel D, Zeitz M, Hering NA, Fromm M, Schulzke JD, Bücker R (2011) Oral and fecal Campylobacter concisus strains perturb barrier function by apoptosis induction in HT-29/B6 intestinal epithelial cells. PLoS ONE 6:e23858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yamazaki Y, Tokumasu R, Kimura H, Tsukita S (2011) Role of claudin species-specific dynamics in reconstitution and remodeling of the zonula occludens. Mol Biol Cell 22:1495–1504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293

    Article  CAS  PubMed  Google Scholar 

  11. Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886

    Article  CAS  PubMed  Google Scholar 

  12. Brandner JM, Kief S, Grund C, Rendl M, Houdek P, Kuhn C, Tschachler E, Franke WW, Moll I (2002) Organization and formation of the tight junction system in human epidermis and cultured keratinocytes. Eur J Cell Biol 81:253–263

    Article  CAS  PubMed  Google Scholar 

  13. Rozlomiy VL, Markov AG (2010) Effect of interleukin-1β on the expression of tight junction proteins in the culture of HaCaT keratinocytes. Bull Exp Biol Med 149:280–283

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Li Q, Geng S (2019) All-trans retinoic acid alters the expression of the tight junction proteins Claudin-1 and -4 and epidermal barrier function-associated genes in the epidermis. Int J Mol Med 43:1789–1805

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Yokoyama S, Tachibana K, Nakanishi H, Yamamoto Y, Irie K, Mandai K, Nagafuchi A, Monden M, Takai Y (2001) alpha-catenin-independent recruitment of ZO-1 to nectin-based cell-cell adhesion sites through afadin. Mol Biol Cell 12:1595–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hartsock A, Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778:660–669

    Article  CAS  PubMed  Google Scholar 

  17. Hämäläinen L, Soini Y, Pasonen-Seppänen S, Siponen M (2019) Alterations in the expression of EMT-related proteins claudin-1, claudin-4 and claudin-7, E-cadherin, TWIST1 and ZEB1 in oral lichen planus. J Oral Pathol Med 48:735–744

    Article  PubMed  CAS  Google Scholar 

  18. Bergqvist C, Ezzedine K (2019) Vitamin D and the skin: what should a dermatologist know? G Ital Dermatol Venereol 154:669–680

    Article  PubMed  Google Scholar 

  19. Holick MF (2009) Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 19:73–78

    Article  PubMed  Google Scholar 

  20. Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ (2010) Vitamin D: metabolism. Endocrinol Metab Clin North Am 39:243–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fathi N, Ahmadian E, Shahi S, Roshangar L, Khan H, Kouhsoltani M, Maleki Dizaj S, Sharifi S (2019) Role of vitamin D and vitamin D receptor (VDR) in oral cancer. Biomed Pharmacother 109:391–401

    Article  CAS  PubMed  Google Scholar 

  22. Martin NG, Rigterink T, Adamji M, Wall CL, Day AS (2019) Single high-dose oral vitamin D3 treatment in New Zealand children with inflammatory bowel disease. Transl Pediatr 8:35–41

    Article  PubMed  PubMed Central  Google Scholar 

  23. Aral K, Alkan BA, Saraymen R, Yay A, Şen A, Önder G (2015) Therapeutic effects of systemic vitamin k2 and vitamin d3 on gingival inflammation and alveolar bone in rats with experimentally induced periodontitis. J Periodontol 86:666–673

    Article  PubMed  Google Scholar 

  24. Wadhwa B, Relhan V, Goel K, Kochhar AM, Garg VK (2015) Vitamin D and skin diseases: a review. Indian J Dermatol Venereol Leprol 81:344–355

    Article  PubMed  Google Scholar 

  25. Bijlsma MF, Roelink H (2017) Skin-derived vitamin D(3) protects against basal cell carcinoma. J Invest Dermatol 137:2469–2471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lebwohl M (2003) Psoriasis. Lancet 361:1197–1204

    Article  PubMed  Google Scholar 

  27. Kurashige Y, Saitoh M, Nishimura M, Noro D, Kaku T, Igarashi S, Takuma T, Arakawa T, Inoue T, Abiko Y (2008) Profiling of differentially expressed genes in porcine epithelial cells derived from periodontal ligament and gingiva by DNA microarray. Arch Oral Biol 53:437–442

    Article  CAS  PubMed  Google Scholar 

  28. Yoshida K, Uehara O, Kurashige Y, Paudel D, Onishi A, Neopane P, Hiraki D, Morikawa T, Harada F, Takai R, Sato J, Saitoh M, Abiko Y (2021) Direct reprogramming of epithelial cell rests of malassez into mesenchymal-like cells by epigenetic agents. Sci Rep 11:1852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  30. Zhang XM, Huang Y, Zhang K, Qu LH, Cong X, Su JZ, Wu LL, Yu GY, Zhang Y (2018) Expression patterns of tight junction proteins in porcine major salivary glands: a comparison study with human and murine glands. J Anat 233:167–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yuan FN, Valiyaparambil J, Woods MC, Tran H, Pant R, Adams JS, Mallya SM (2014) Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo. Int J Oncol 44:1625–1633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bikle DD (2010) Vitamin D and the skin. J Bone Miner Metab 28:117–130

    Article  CAS  PubMed  Google Scholar 

  33. Kommagani R, Whitlatch A, Leonard MK, Kadakia MP (2010) p73 is essential for vitamin D-mediated osteoblastic differentiation. Cell Death Differ 17:398–407

    Article  CAS  PubMed  Google Scholar 

  34. Jugert FK, Roos TC, Notzon I, Merk HF (1998) Vitamin D3 and its synthetic analogue secocholestra-trien-1,2, 24-triol influence the metabolism and the isomerization of retinoic acid in human keratinocytes. Skin Pharmacol Appl Skin Physiol 11:161–165

    Article  CAS  PubMed  Google Scholar 

  35. Tone T, Eto H, Katsuoka K, Nishioka K, Nishiyama S (1991) Suppression of gamma-interferon induced HLA-DR antigen expression on normal and transformed keratinocytes by 1,25 (OH)2 vitamin D3. Nihon Hifuka Gakkai Zasshi 101:519–525

    CAS  PubMed  Google Scholar 

  36. Yuki T, Hachiya A, Kusaka A, Sriwiriyanont P, Visscher MO, Morita K, Muto M, Miyachi Y, Sugiyama Y, Inoue S (2011) Characterization of tight junctions and their disruption by UVB in human epidermis and cultured keratinocytes. J Invest Dermatol 131:744–752

    Article  CAS  PubMed  Google Scholar 

  37. Hatakeyama S, Yaegashi T, Oikawa Y, Fujiwara H, Mikami T, Takeda Y, Satoh M (2006) Expression pattern of adhesion molecules in junctional epithelium differs from that in other gingival epithelia. J Periodontal Res 41:322–328

    Article  CAS  PubMed  Google Scholar 

  38. Hatakeyama S, Ishida K, Takeda Y (2010) Changes in cell characteristics due to retinoic acid; specifically, a decrease in the expression of claudin-1 and increase in claudin-4 within tight junctions in stratified oral keratinocytes. J Periodontal Res 45:207–215

    Article  CAS  PubMed  Google Scholar 

  39. Wang K, Pascal LE, Li F, Chen W, Dhir R, Balasubramani GK, DeFranco DB, Yoshimura N, He D, Wang Z (2020) Tight junction protein claudin-1 is downregulated by TGF-β1 via MEK signaling in benign prostatic epithelial cells. Prostate 80:1203–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kojima T, Kohno T, Kubo T, Kaneko Y, Kakuki T, Kakiuchi A, Kurose M, Takano KI, Ogasawara N, Obata K, Nomura K, Miyata R, Konno T, Ichimiya S, Himi T (2017) Regulation of claudin-4 via p63 in human epithelial cells. Ann N Y Acad Sci 1405:25–31

    Article  CAS  PubMed  Google Scholar 

  41. Koli K, Keski-Oja J (1993) Vitamin D3 and calcipotriol enhance the secretion of transforming growth factor-beta 1 and -beta 2 in cultured murine keratinocytes. Growth Factors 8:153–163

    Article  CAS  PubMed  Google Scholar 

  42. Chen H, Lu R, Zhang YG, Sun J (2018) Vitamin D receptor deletion leads to the destruction of tight and adherens junctions in lungs. Tissue Barriers 6:1–13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gorman S, Buckley AG, Ling KM, Berry LJ, Fear VS, Stick SM, Larcombe AN, Kicic A, Hart PH (2017) Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity. Physiol Rep 5:e13371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wu J, He C, Bu J, Luo Y, Yang S, Ye C, Yu S, He B, Yin Y, Yang X (2020) Betaine attenuates LPS-induced downregulation of occludin and claudin-1 and restores intestinal barrier function. BMC Vet Res 16:75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gan H, Wang G, Hao Q, Wang QJ, Tang H (2013) Protein kinase D promotes airway epithelial barrier dysfunction and permeability through down-regulation of claudin-1. J Biol Chem 288:37343–37354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu L, Oshima T, Tomita T, Ohda Y, Fukui H, Watari J, Miwa H (2016) Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model. J Gastroenterol 51:1040–1049

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Dentistry, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu, Ishikari, Hokkaido, 0610293, Japan

    Erika Minowa, Yoshihito Kurashige, Syed Taufiqul Islam, Sayaka Sakakibara, Yunosuke Okada, Yusuke Fujita, Dembereldorj Bolortsetseg, Yuji Murai & Masato Saitoh

  2. Division of Oral Medicine and Pathology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari, Hokkaido, Japan

    Koki Yoshida & Yoshihiro Abiko

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  1. Erika Minowa
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Correspondence to Masato Saitoh.

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Minowa, E., Kurashige, Y., Islam, S.T. et al. Increased integrity of cell–cell junctions accompanied by increased expression of claudin 4 in keratinocytes stimulated with vitamin D3. Med Mol Morphol 54, 346–355 (2021). https://doi.org/10.1007/s00795-021-00299-1

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