Advertisement

Molecular Medicine

, Volume 18, Issue 2, pp 194–200 | Cite as

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

  • Teresina Laragione
  • Anish Shah
  • Pércio S. Gulko
Research Article

Abstract

Serum levels of vitamin D levels are commonly reduced in patients with rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. We recently identified a new vitamin D receptor transcriptional signature in synovial tissues from rats with mild and nonerosive arthritis, suggesting a vitamin D-mediated protective effect. In the present study, we address the hypothesis that part of the vitamin D protective effect is mediated via interference with fibroblast-like synoviocyte (FLS) invasive properties, an in vitro cellular phenotype that correlates with radiographic and histological damage in pristane-induced arthritis and RA. FLSs derived from DA rats with pristane-induced arthritis and RA patients were studied in an in vitro model of invasion through a collagen-rich barrier (Matrigel) over a 24-h period, in the presence or absence of calcitriol, an active form of vitamin D. Matrix metalloprotease (MMP) expression levels were analyzed with zymography and quantitative real-time polymerase chain reaction, and the cytoskeleton was studied with immunofluorescense microscopy. Calcitriol significantly inhibited DA and RA FLS invasion by 54% and 53%, respectively. Calcitriol also reduced interleukin (IL)-1β-induced expression of MMP-1 by 95% in DA FLSs and by 73.5% in RA FLS. Calcitriol treatment reduced actin cytoskeleton reorganization, reduced polarized formation of lamellipodia and reduced colocalization of phosphorylated focal adhesion kinase (p-FAK) with lamellipodia, all consistent with reduced cell ability to move and invade. In conclusion, we identified a new effect of calcitriol in FLS invasion. This discovery suggests that the reduced serum levels of vitamin D and its metabolites commonly seen in RA might increase risk for FLS-mediated cartilage and bone invasion and erosions. Treatment with vitamin D or its analogs has the potential to become a helpful adjuvant aimed at preventing or reducing joint destruction.

Notes

Acknowledgments

The authors wish to thank Cathleen Mason and Mary Keogh of the Feinstein Institute’s Tissue Donation Program for their assistance in obtaining the RA synovial tissues used in this study.

This study was funded by the National Institutes of Health, grants R01-AR46213, R01-AR052439 (NIAMS) and R01-AI54348 (NIAID), to PS Gulko.

References

  1. 1.
    Seldin MF, Amos CI, Ward R, Gregersen PK. (1999) The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 42:1071–9.CrossRefGoogle Scholar
  2. 2.
    Gulko PS, Winchester RJ. (2001) Rheumatoid arthritis. In: Samter’s Immunologic Diseases. Austen KF, Frank MM, Atkinson JP, Cantor H (eds.) Lippincott, Williams & Wilkins, Baltimore, MD, pp. 427–63.Google Scholar
  3. 3.
    Wolfe F, et al. (1994) The mortality of rheumatoid arthritis. Arthritis Rheum. 37:481–94.CrossRefGoogle Scholar
  4. 4.
    Gossec L, et al. (2004) Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study. Ann. Rheum. Dis. 63:675–80.CrossRefGoogle Scholar
  5. 5.
    Brenner M, Linge CP, Li W, Gulko PS. (2011) Increased synovial expression of nuclear receptors correlates with arthritis protection: a possible novel genetically regulated homeostatic mechanism. Arthritis Rheum. 63:2918–29.CrossRefGoogle Scholar
  6. 6.
    Tuckey RC, et al. (2008) Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc. FEBS J. 275:2585–96.CrossRefGoogle Scholar
  7. 7.
    Schuster I. (2011) Cytochromes P450 are essential players in the vitamin D signaling system. Biochim. Biophys. Acta. 1814:186–99.CrossRefGoogle Scholar
  8. 8.
    Kerr GS, et al. (2011) Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J. Rheumatol. 38:53–9.CrossRefGoogle Scholar
  9. 9.
    Rossini M, et al. (2010) Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res. Ther. 12:R216.CrossRefGoogle Scholar
  10. 10.
    Craig SM, et al. (2010) Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J. Rheumatol. 37:275–81.CrossRefGoogle Scholar
  11. 11.
    Moghaddami M, et al. (2011) Efficacy and mechanisms of action of vitamin D in experimental polyarthritis. Immunol. Cell. Biol. 2011, Mar 29 [Epub ahead of print].Google Scholar
  12. 12.
    Cantorna MT, Hayes CE, DeLuca HF. (1998) 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J. Nutr. 128:68–72.CrossRefGoogle Scholar
  13. 13.
    Szeto FL, et al. (2007) Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts. J. Steroid. Biochem. Mol. Biol. 103:563–6.CrossRefGoogle Scholar
  14. 14.
    Tetlow LC, Woolley DE. (1999) The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion. Arthritis Res. 1:63–70.CrossRefGoogle Scholar
  15. 15.
    Colin EM, et al. (2010) 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 62:132–42.CrossRefGoogle Scholar
  16. 16.
    Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. (2007) Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179:1634–47.CrossRefGoogle Scholar
  17. 17.
    Muller-Ladner U, et al. (1996) Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149:1607–15.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Bartok B, Firestein GS. (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233:233–55.CrossRefGoogle Scholar
  19. 19.
    van der Heijde D, Landewe R, van Vollenhoven R, Fatenejad S, Klareskog L. (2008) Level of radiographic damage and radiographic progression are determinants of physical function: a longitudinal analysis of the TEMPO trial. Ann. Rheum. Dis. 67:1267–70.CrossRefGoogle Scholar
  20. 20.
    Laragione T, Brenner M, Mello A, Symons M, Gulko PS. (2008) The arthritis severity locus Cia5d is a novel genetic regulator of the invasive properties of synovial fibroblasts. Arthritis Rheum. 58:2296–306.CrossRefGoogle Scholar
  21. 21.
    Tolboom TC, et al. (2005) Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum. 52:1999–2002.CrossRefGoogle Scholar
  22. 22.
    Vingsbo C, et al. (1996) Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am. J. Pathol. 149:1675–83.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Brenner M, et al. (2005) The non-MHC quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation and joint damage. Arthritis Rheum. 52:322–32.CrossRefGoogle Scholar
  24. 24.
    Arnett FC, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–24.CrossRefGoogle Scholar
  25. 25.
    Laragione T, Gulko PS. (2010) mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol. Med. 16:352–8.CrossRefGoogle Scholar
  26. 26.
    Laragione T, Brenner M, Sherry B, Gulko PS. (2011) CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis. Arthritis Rheum. 63:3274–83.CrossRefGoogle Scholar
  27. 27.
    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. 25:402–8.CrossRefGoogle Scholar
  28. 28.
    van Zeben D, Hazes JM, Zwinderman AH, Vandenbroucke JP, Breedveld FC. (1993) Factors predicting outcome of rheumatoid arthritis: results of a followup study. J. Rheumatol. 20:1288–96.PubMedGoogle Scholar
  29. 29.
    Welsing PM, van Gestel AM, Swinkels HL, Kiemeney LA, van Riel PL. (2001) The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum. 44:2009–17.CrossRefGoogle Scholar
  30. 30.
    Drossaers-Bakker KW, et al. (1999) Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis Rheum. 42:1854–60.CrossRefGoogle Scholar
  31. 31.
    Combe B, et al. (2001) Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study. Arthritis Rheum. 44:1736–43.CrossRefGoogle Scholar
  32. 32.
    Boissier MC, Chiocchia G, Fournier C. (1992) Combination of cyclosporine A and calcitriol in the treatment of adjuvant arthritis. J. Rheumatol. 19:754–7.PubMedGoogle Scholar
  33. 33.
    Tsuji M, Fujii K, Nakano T, Nishii Y. (1994) 1 Alpha-hydroxyvitamin D3 inhibits type II collagen-induced arthritis in rats. FEBS Lett. 337:248–50.CrossRefGoogle Scholar
  34. 34.
    Larsson P, Mattsson L, Klareskog L, Johnsson C. (1998) A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. Clin. Exp. Immunol. 114:277–83.CrossRefGoogle Scholar
  35. 35.
    Cunnane G, et al. (2001) Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis. Arthritis Rheum. 44:1744–53.CrossRefGoogle Scholar
  36. 36.
    Machesky LM. (2008) Lamellipodia and filopodia in metastasis and invasion. FEBS Lett. 582:2102–11.CrossRefGoogle Scholar
  37. 37.
    Smith SJ, Hayes ME, Selby PL, Mawer EB. (1999) Autocrine control of vitamin D metabolism in synovial cells from arthritic patients. Ann. Rheum. Dis. 58:372–8.CrossRefGoogle Scholar
  38. 38.
    Sung V, Feldman D. (2000) 1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. Mol. Cell. Endocrinol. 164:133–43.CrossRefGoogle Scholar
  39. 39.
    Sundaram S, et al. (2006) QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells. Mol. Cancer Ther 5:2806–14.CrossRefGoogle Scholar
  40. 40.
    Palmer HG, et al. (2001) Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J. Cell. Biol. 154:369–87.CrossRefGoogle Scholar
  41. 41.
    Tokar EJ, Webber MM. (2005) Cholecalciferol (vitamin D3) inhibits growth and invasion by up-regulating nuclear receptors and 25-hydroxylase (CYP27A1) in human prostate cancer cells. Clin. Exp. Metastasis. 22:275–84.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Teresina Laragione
    • 1
  • Anish Shah
    • 1
  • Pércio S. Gulko
    • 1
    • 2
  1. 1.Laboratory of Experimental Rheumatology, Center for Genomics and Human GeneticsFeinstein Institute for Medical ResearchManhassetUSA
  2. 2.Elmezzi Graduate School of Molecular MedicineManhassetUSA

Personalised recommendations