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Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma

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Abstract

Vitamin D analogues can reduce TGF-β pro-fibrotic signaling in dermal fibroblasts, but they may also induce a potentially pro-fibrotic thymic stromal lymphopoietin (TSLP)-dependent Th2 cytokine local response. We have analyzed the net effect of topical vitamin D analogue calcipotriol (CPT) on the cytokine profile and the development of fibrosis in experimental model of bleomycin-induced fibrosis. Mice were simultaneously treated with topical CPT or vehicle cream and skin fibrosis was measured by collagen deposition, Masson’s trichrome staining and hydroxyproline content. Cytokine and TSLP gene expression was evaluated by quantitative RT-PCR. We showed that in bleomycin injected skin, CPT administration significantly enhanced TSLP and IL-13 gene expression, but did not modify the expression of other cytokines. Skin fibrosis and hydroxyproline content were significantly reduced in CPT compared to vehicle-treated mice. In normal skin, topical administration of CPT lacked a direct pro-fibrotic effect. Our results demonstrate that topical CPT superinduces the expression of the TSLP/IL-13 Th2 axis in fibrotic skin, but it has a net anti-fibrotic effect. These data support the therapeutic use of topical vitamin D analogues for skin fibrosis.

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References

  1. Bossini-Castillo L, Broen JC, Simeon CP, Beretta L, Vonk MC, Ortego-Centeno N, Espinosa G, Carreira P, Camps MT, Navarrete N, González-Escribano MF et al (2011) A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort. Ann Rheum Dis 70:638–641

    Article  PubMed  CAS  Google Scholar 

  2. Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeón CP, Beretta L, Vonk MC, Callejas JL, Castellví I, Carreira P, García-Hernández FJ et al (2012) A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 21:926–933

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Christmann BR, Mathes A, Affandi AJ, Padilla C, Nazari B, Bujor AM, Stifano G, Lafyatis R (2013) Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor β. Arthritis Rheum 65:1335–1346

    Article  PubMed  CAS  Google Scholar 

  4. Elst EF, Van Suijlekom-Smit LW, Oranje AP (1999) Treatment of linear scleroderma with oral 1,25-dihydroxyvitamin d3 (calcitriol) in seven children. Pediatr Dermatol 16:53–58

    Article  PubMed  CAS  Google Scholar 

  5. Hegyi Z, Zwicker S, Bureik D, Peric M, Koglin S, Batycka-Baran A, Prinz JC, Ruzicka T, Schauber J, Wolf R (2012) Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 “alarmins” psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis. J Invest Dermatol 132:1416–1424

    Article  PubMed  CAS  Google Scholar 

  6. Hulshof MM, Bouwes Bavinck JN, Bergman W, Masclee AA, Heickendorff L, Breedveld FC, Dijkmans BA (2000) Double-blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma. J Am Acad Dermatol 43:1017–1023

    Article  PubMed  CAS  Google Scholar 

  7. Humbert PG, Dupond JL, Rochefort A, Vasselet R, Lucas A, Laurent R, Agache P (1990) Localized scleroderma-response to 1,25-dihydroxyvitamin D3. Clin Exp Dermatol 15:396–398

    Article  PubMed  CAS  Google Scholar 

  8. Li M, Hener P, Zhang Z, Kato S, Metxger D, Chambon P (2006) Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA 103:11736–11741

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Li M, Hener P, Zhang Z, Ganti KP, Metzger D, Chambon P (2009) Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin. J Invest Dermatol 129:498–502

    Article  PubMed  CAS  Google Scholar 

  10. Li Y, Spataro BC, Yang J, Dai C, Liu Y (2005) 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int 68:1500–1510

    Article  PubMed  CAS  Google Scholar 

  11. Meneghin A, Hogaboam CM (2007) Infectious disease, the innate immune response, and fibrosis. J Clin Invest 117:530–538

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Ramirez AM, Wongtrakool C, Welch T, Steinmeyer A, Zugel U, Roman J (2010) Vitamin D inhibition of pro-fibrotic effects of transforming growth factor beta1 in lung fibroblasts and epithelial cells. J Steroid Biochem Mol Biol 118:42–50

    Article  Google Scholar 

  13. Sato-Deguchi E, Imafuku S, Chou B, Ishii K, Hiromatsu K, Nakayama J (2012) Topical vitamin D3 analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions. Br J Dermatol 167:77–84

    Article  PubMed  CAS  Google Scholar 

  14. Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, Li W, Jiao Y, Gu W, Brown M, Postlethwaite AE (2013) 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. J Clin Endocrinol Metab 98:E298–E303

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Uchida M, Shima M, Chikazu D, Fujieda A, Obara K, Suzuki H, Nagai Y, Yamato H, Kawaguchi H (2001) Transcriptional induction of matrix metalloproteinase-13 (collagenase-3) by 1alpha,25-dihydroxyvitamin D3 in mouse osteoblastic MC3T3-E1 cells. J Bone Miner Res 16:221–230

    Article  PubMed  CAS  Google Scholar 

  16. Usategui A, Criado G, Izquierdo E, Del Rey MJ, Carreira PE, Ortiz P, Leonard WJ, Pablos JL (2013) A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis. Ann Rheum Dis 72:2018–2023

    Article  PubMed  CAS  Google Scholar 

  17. Vacca A, Cormier C, Mathie A, Kahan A, Allanore Y (2011) Vitamin D levels and potential impact in systemic sclerosis. Clin Exp Rheumatol 29:1024–1031

    PubMed  Google Scholar 

  18. Wynn TA (2011) Integrating mechanisms of pulmonary fibrosis. J Exp Med 208:1339–1350

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Yamamoto T, Nishioka K (2005) Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: current update and future perspective. Exp Dermatol 14:81–95

    Article  PubMed  CAS  Google Scholar 

  20. Zerr P, Vollath S, Palumbo-Zerr K, Tomcik M,Huang J,Distler A, Beyer C, Dees C, Gela K, Distler O, Schett G, Distler JH (2014) Vitamin D receptor regulates TGF-β signalling in systemic sclerosis. Ann Rheum Dis [Epub ahead of print]. doi:10.1136/annrheumdis-2013-204378

  21. Zhang GY, Cheng T, Luan Q, Liao T, Nie CL, Zheng X, Xie XG, Gao WY (2011) Vitamin D: a novel therapeutic approach for keloid, an in vitro analysis. Br J Dermatol 164:729–737

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Vanessa Miranda for excellent technical assistance. This work was supported by Fondo de Investigacion Sanitaria (PI12/439, RIER RD12/09/016). GC is a recipient of a Miguel Servet fellowship (CP07/250) from the Instituto de Salud Carlos III.

Conflict of interest

The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Servicio de Reumatología, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041, Madrid, Spain

    Alicia Usategui, Gabriel Criado, Manuel J. Del Rey, Regina Faré & José L. Pablos

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  1. Alicia Usategui
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  2. Gabriel Criado
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  3. Manuel J. Del Rey
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  4. Regina Faré
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  5. José L. Pablos
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Correspondence to José L. Pablos.

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Usategui, A., Criado, G., Del Rey, M.J. et al. Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma. Arch Dermatol Res 306, 757–761 (2014). https://doi.org/10.1007/s00403-014-1466-6

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  • DOI: https://doi.org/10.1007/s00403-014-1466-6

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