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PPAR Research
Volume 2015 (2015), Article ID 124624, 12 pages
http://dx.doi.org/10.1155/2015/124624
Review Article

The Role of PPAR Gamma in Systemic Sclerosis

1Serviço de Reumatologia do Hospital das Clínicas da Universidade Federal de Pernambuco (HC-UFPE), 50670-901 Recife, PE, Brazil
2Laboratório de Imunomodulação e Novas Abordagens Terapêuticas da Universidade Federal de Pernambuco (LINAT-UFPE), 50670-901 Recife, PE, Brazil
3Laboratório de Planejamento e Síntese de Fármacos da Universidade Federal de Pernambuco (LPSF-UFPE), 50670-901 Recife, PE, Brazil

Received 11 February 2015; Revised 23 April 2015; Accepted 23 April 2015

Academic Editor: Tom Hsun-Wei Huang

Copyright © 2015 Andréa Tavares Dantas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Y.-L. Deng, X.-Z. Xiong, and N.-S. Cheng, “Organ fibrosis inhibited by blocking transforming growth factor-beta signaling via peroxisome proliferator-activated receptor gamma agonists,” Hepatobiliary and Pancreatic Diseases International, vol. 11, no. 5, pp. 467–478, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. J. A. Varga and M. Trojanowska, “Fibrosis in systemic sclerosis,” Rheumatic Disease Clinics of North America, vol. 34, no. 1, pp. 115–143, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Wei, S. Bhattacharyya, W. G. Tourtellotte, and J. Varga, “Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy,” Autoimmunity Reviews, vol. 10, no. 5, pp. 267–275, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. R. T. Kendall and C. A. Feghali-Bostwick, “Fibroblasts in fibrosis: novel roles and mediators,” Frontiers in Pharmacology, vol. 5, article 123, 2014. View at Publisher · View at Google Scholar
  5. J. Rosenbloom, S. V. Castro, and S. A. Jimenez, “Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies,” Annals of Internal Medicine, vol. 152, no. 3, pp. 159–166, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Wei, S. Bhattacharyya, and J. Varga, “Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis,” Current Opinion in Rheumatology, vol. 22, no. 6, pp. 671–676, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. G. C. Blobe, W. P. Schiemann, and H. F. Lodish, “Role of transforming growth factor β in human disease,” The New England Journal of Medicine, vol. 342, no. 18, pp. 1350–1358, 2000. View at Publisher · View at Google Scholar · View at Scopus
  8. R. Derynck and Y. E. Zhang, “Smad-dependent and Smad-independent pathways in TGF-β family signalling,” Nature, vol. 425, no. 6958, pp. 577–584, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. J. Varga and B. Pasche, “Transforming growth factor beta as a therapeutic target in systemic sclerosis,” Nature reviews. Rheumatology, vol. 5, no. 4, pp. 200–206, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Bhattacharyya, J. Wei, W. G. Tourtellotte, M. Hinchcliff, C. G. Gottardi, and J. Varga, “Fibrosis in systemic sclerosis: common and unique pathobiology,” Fibrogenesis and Tissue Repair, vol. 5, no. 1, article S18, 2012. View at Publisher · View at Google Scholar · View at Scopus
  11. T. A. Wynn, “Cellular and molecular mechanisms of fibrosis,” Journal of Pathology, vol. 214, no. 2, pp. 199–210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Lehrke and M. A. Lazar, “The many faces of PPARgamma,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. J. Wei, S. Bhattacharyya, M. Jain, and J. Varga, “Regulation of matrix remodeling by peroxisome proliferator-activated receptor-γ: a novel link between metabolism and fibrogenesis,” Open Rheumatology Journal, vol. 6, no. 1, pp. 103–115, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. H. F. Lakatos, T. H. Thatcher, R. M. Kottmann, T. M. Garcia, R. P. Phipps, and P. J. Sime, “The role of PPARs in lung fibrosis,” PPAR Research, vol. 2007, Article ID 71323, 10 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. S. A. Brietzke, “Oral antihyperglycemic treatment options for type 2 diabetes mellitus,” Medical Clinics of North America, vol. 99, no. 1, pp. 87–106, 2015. View at Publisher · View at Google Scholar
  16. C. Bosetti, V. Rosato, D. Buniato, A. Zambon, C. La Vecchia, and G. Corrao, “Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis,” The Oncologist, vol. 18, no. 2, pp. 148–156, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. Z. Zhu, Y. Jiang, and T. Ding, “Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials,” Bone, vol. 68, pp. 115–123, 2014. View at Publisher · View at Google Scholar
  18. E. M. Zardi, L. Navarini, G. Sambataro et al., “Hepatic PPARs: their role in liver physiology, fibrosis and treatment,” Current Medicinal Chemistry, vol. 20, no. 27, pp. 3370–3396, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. L. F. da Rocha Junior, A. T. Dantas, Â. L. B. P. Duarte, M. J. B. de Melo Rego, I. D. R. Pitta, and M. G. D. R. Pitta, “PPARγ agonists in adaptive immunity: what do immune disorders and their models have to tell us?” PPAR Research, vol. 2013, Article ID 519724, 9 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. J. T. M. Tan, S. V. McLennan, W. W. Song et al., “Connective tissue growth factor inhibits adipocyte differentiation,” American Journal of Physiology—Cell Physiology, vol. 295, no. 3, pp. C740–C751, 2008. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Wu, D. S. Melichian, E. Chang, M. Warner-Blankenship, A. K. Ghosh, and J. Varga, “Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-γ,” American Journal of Pathology, vol. 174, no. 2, pp. 519–533, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Wei, A. K. Ghosh, J. L. Sargent et al., “PPARγ downregulation by TGFß in in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis,” PLoS ONE, vol. 5, no. 11, Article ID e13778, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. K. Lakota, J. Wei, M. Carns et al., “Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker?” Arthritis Research and Therapy, vol. 14, no. 3, article R102, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Ramirez, E. N. Ballard, and J. Roman, “TGFβ1 controls PPARγ expression, transcriptional potential, and activity, in part, through Smad3 signaling in murine lung fibroblasts,” PPAR Research, vol. 2012, Article ID 375876, 7 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. A. K. Ghosh, S. Bhattacharyya, G. Lakos, S.-J. Chen, Y. Mori, and J. Varga, “Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor γ,” Arthritis & Rheumatism, vol. 50, no. 4, pp. 1305–1318, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. A. K. Ghosh, S. Bhattacharyya, J. Wei et al., “Peroxisome proliferator-activated receptor-γ abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator,” The FASEB Journal, vol. 23, no. 9, pp. 2968–2977, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Wei, H. Zhu, K. Komura et al., “A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses,” Annals of the Rheumatic Diseases, vol. 73, no. 2, pp. 446–454, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. X. Li, H. Kimura, K. Hirota et al., “Hypoxia reduces the expression and anti-inflammatory effects of peroxisome proliferator-activated receptor-γ in human proximal renal tubular cells,” Nephrology Dialysis Transplantation, vol. 22, no. 4, pp. 1041–1051, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. S. E. Ross, N. Hemati, K. A. Longo et al., “Inhibition of adipogenesis by Wnt signaling,” Science, vol. 289, no. 5481, pp. 950–953, 2000. View at Publisher · View at Google Scholar · View at Scopus
  30. K. M. Ajuwon and M. E. Spurlock, “Adiponectin inhibits LPS-induced NF-κB activation and IL-6 production and increases PPARγ2 expression in adipocytes,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 288, no. 5, pp. R1220–R1225, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. M. S. Shafiei, S. Shetty, P. E. Scherer, and D. C. Rockey, “Adiponectin regulation of stellate cell activation via PPARγ-dependent and -independent mechanisms,” The American Journal of Pathology, vol. 178, no. 6, pp. 2690–2699, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. Y.-W. Qin, P. Ye, J.-Q. He, L. Sheng, L.-Y. Wang, and J. Du, “Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a Western-style diet by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels,” Acta Pharmacologica Sinica, vol. 31, no. 10, pp. 1350–1358, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Miana, N. de las Heras, C. Rodriguez et al., “Effect of eplerenone on hypertension-associated renal damage in rats: potential role of peroxisome proliferator activated receptor gamma(PPAR-γ),” Journal of Physiology and Pharmacology, vol. 62, no. 1, pp. 87–94, 2011. View at Google Scholar · View at Scopus
  34. Z.-Z. Zhang, Q.-H. Shang, H.-Y. Jin et al., “Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice,” Journal of Translational Medicine, vol. 11, no. 1, article 229, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Zambrano, A. J. Blanca, M. V. Ruiz-Armenta et al., “L-carnitine attenuates the development of kidney fibrosis in hypertensive rats by upregulating PPAR-γ,” American Journal of Hypertension, vol. 27, no. 3, pp. 460–470, 2014. View at Publisher · View at Google Scholar · View at Scopus
  36. K. Sun, Q. Wang, and X.-H. Huang, “PPAR gamma inhibits growth of rat hepatic stellate cells and TGF betainduced connective tissue growth factor expression,” Acta Pharmacologica Sinica, vol. 27, no. 6, pp. 715–723, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. G.-Y. Zhang, T. Cheng, M.-H. Zheng et al., “Activation of peroxisome proliferator-activated receptor-γ inhibits transforming growth factor-β1 induction of connective tissue growth factor and extracellular matrix in hypertrophic scar fibroblasts in vitro,” Archives of Dermatological Research, vol. 301, no. 7, pp. 515–522, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. C. Zhao, W. Chen, L. Yang, L. Chen, S. A. Stimpson, and A. M. Diehl, “PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells,” Biochemical and Biophysical Research Communications, vol. 350, no. 2, pp. 385–391, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. M. Zhu, L. Flynt, S. Ghosh et al., “Anti-inflammatory effects of thiazolidinediones in human airway smooth muscle cells,” American Journal of Respiratory Cell and Molecular Biology, vol. 45, no. 1, pp. 111–119, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. H. A. Burgess, L. E. Daugherty, T. H. Thatcher et al., “PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 288, no. 6, pp. L1146–L1153, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. H.-F. Pan, X.-F. Zhao, H. Yuan et al., “Decreased serum IL-22 levels in patients with systemic lupus erythematosus,” Clinica Chimica Acta, vol. 401, no. 1-2, pp. 179–180, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. E. S. White, R. G. Atrasz, B. Hu et al., “Negative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10),” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 1, pp. 112–121, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. S. J. Lee, E. K. Yang, and S. G. Kim, “Peroxisome proliferator-activated receptor-γ and retinoic acid X receptor α represses the TGFβ1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation,” Molecular Pharmacology, vol. 70, no. 1, pp. 415–425, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. Li, X. Wen, B. C. Spataro, K. Hu, C. Dai, and Y. Liu, “Hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-γ agonists,” Journal of the American Society of Nephrology, vol. 17, no. 1, pp. 54–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Zhao, Y. Huang, J. He et al., “Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates airway inflammation by inhibiting the proliferation of effector T cells in a murine model of neutrophilic asthma,” Immunology Letters, vol. 157, no. 1-2, pp. 9–15, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. B. Guo, D. Koya, M. Isono, T. Sugimoto, A. Kashiwagi, and M. Haneda, “Peroxisome proliferator-activated receptor-γ ligands inhibit TGF-β 1-induced fibronectin expression in glomerular mesangial cells,” Diabetes, vol. 53, no. 1, pp. 200–208, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. J. E. Milam, V. G. Keshamouni, S. H. Phan et al., “PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 294, no. 5, pp. L891–L901, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. H. E. Ferguson, A. Kulkarni, G. M. Lehmann et al., “Electrophilic peroxisome proliferator-activated receptor-γ ligands have potent antifibrotic effects in human lung fibroblasts,” American Journal of Respiratory Cell and Molecular Biology, vol. 41, no. 6, pp. 722–730, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. A. A. Kulkarni, T. H. Thatcher, K. C. Olsen, S. B. Maggirwar, R. P. Phipps, and P. J. Sime, “PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis,” PLoS ONE, vol. 6, no. 1, Article ID e15909, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. S. H. Phan, “The myofibroblast in pulmonary fibrosis,” Chest, vol. 122, no. 6, supplement, pp. 286s–289s, 2002. View at Google Scholar · View at Scopus
  51. E. B. Meltzer and P. W. Noble, “Idiopathic pulmonary fibrosis,” Orphanet Journal of Rare Diseases, vol. 3, no. 1, article 8, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. T. H.-W. Huang, V. Razmovski-Naumovski, B. P. Kota, D. S.-H. Lin, and B. D. Roufogalis, “The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases,” Respiratory Research, vol. 6, article 102, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. G. S. Bogatkevich, K. B. Highland, T. Akter, and R. M. Silver, “The PPARγ agonist rosiglitazone is antifibrotic for scleroderma lung fibroblasts: mechanisms of action and differential racial effects,” Pulmonary Medicine, vol. 2012, Article ID 545172, 9 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. D. A. Culver, B. P. Barna, B. Raychaudhuri et al., “Peroxisome proliferator-activated receptor γ activity is deficient in alveolar macrophages in pulmonary sarcoidosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 30, no. 1, pp. 1–5, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. T. L. Bonfield, C. F. Farver, B. P. Barna et al., “Peroxisome proliferator-activated receptor-γ is deficient in alveolar macrophages from patients with alveolar proteinosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 29, no. 6, pp. 677–682, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. Q. Lin, L.-P. Fang, W.-W. Zhou, and X.-M. Liu, “Rosiglitazone inhibits migration, proliferation, and phenotypic differentiation in cultured human lung fibroblasts,” Experimental Lung Research, vol. 36, no. 2, pp. 120–128, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. A. L. Tatler and G. Jenkins, “TGF-beta activation and lung fibrosis,” Proceedings of the American Thoracic Society, vol. 9, no. 3, pp. 130–136, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Nakerakanti and M. Trojanowska, “The role of TGF-β receptors in fibrosis,” The Open Rheumatology Journal, vol. 6, no. 1, pp. 156–162, 2012. View at Publisher · View at Google Scholar · View at Scopus
  59. X. Tan, H. Dagher, C. A. Hutton, and J. E. Bourke, “Effects of PPARγ ligands on TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells,” Respiratory Research, vol. 11, article 21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. Y. Aoki, T. Maeno, K. Aoyagi et al., “Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis,” Respiration, vol. 77, no. 3, pp. 311–319, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. T. Genovese, S. Cuzzocrea, R. Di Paola et al., “Effect of rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 on bleomycin-induced lung injury,” European Respiratory Journal, vol. 25, no. 2, pp. 225–234, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Samah, A. E.-R. El-Aidy, M. K. Tawfik, and M. M. S. Ewais, “Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats,” European Journal of Pharmacology, vol. 689, no. 1–3, pp. 186–193, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Y. Jin, S. M. Bok, Y. M. Han et al., “Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: assessed by micro-computed tomography and pathologic scores,” European Journal of Radiology, vol. 81, no. 8, pp. 1901–1906, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. E. J. Choi, G. Y. Jin, S. M. Bok, Y. M. Han, Y. S. Lee, and M. J. Jung, “Serial micro-CT assessment of the therapeutic effects of rosiglitazone in a bleomycin-induced lung fibrosis mouse model,” Korean Journal of Radiology, vol. 15, no. 4, pp. 448–455, 2014. View at Google Scholar
  65. J. J. Tomasek, G. Gabbiani, B. Hinz, C. Chaponnier, and R. A. Brown, “Myofibroblasts and mechano: regulation of connective tissue remodelling,” Nature Reviews Molecular Cell Biology, vol. 3, no. 5, pp. 349–363, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. A. K. Ghosh, S. E. Quaggin, and D. E. Vaughan, “Molecular basis of organ fibrosis: potential therapeutic approaches,” Experimental Biology and Medicine, vol. 238, no. 5, pp. 461–481, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. G.-Y. Zhang, T. Cheng, M.-H. Zheng et al., “Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist inhibits transforming growth factor-beta1 and matrix production in human dermal fibroblasts,” Journal of Plastic, Reconstructive and Aesthetic Surgery, vol. 63, no. 7, pp. 1209–1216, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Kapoor, F. Kojima, L. Yang, and L. J. Crofford, “Sequential induction of pro- and anti-inflammatory prostaglandins and peroxisome proliferators-activated receptor-gamma during normal wound healing: a time course study,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 76, no. 2, pp. 103–112, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. E. G. Gonzalez, E. Selvi, E. Balistreri et al., “Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 71, no. 9, pp. 1545–1551, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. A. K. Ghosh, J. Wei, M. Wu, and J. Varga, “Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-γ,” Biochemical and Biophysical Research Communications, vol. 374, no. 2, pp. 231–236, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. X. Li, J. Mai, A. Virtue et al., “IL-35 is a novel responsive anti-inflammatory cytokine—a new system of categorizing anti-inflammatory cytokines,” PLoS ONE, vol. 7, no. 3, Article ID e33628, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Kapoor, M. McCann, S. Liu et al., “Loss of peroxisome proliferator-activated receptor γ in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis,” Arthritis and Rheumatism, vol. 60, no. 9, pp. 2822–2829, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. W. Sha, K. Thompson, J. South, M. Baron, and A. Leask, “Loss of PPARγ expression by fibroblasts enhances dermal wound closure,” Fibrogenesis and Tissue Repair, vol. 5, no. 1, article 5, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Krieg and K. Takehara, “Skin disease: a cardinal feature of systemic sclerosis,” Rheumatology, vol. 48, supplement 3, pp. iii14–iii18, 2009. View at Google Scholar · View at Scopus
  75. A. U. Wells, V. Steen, and G. Valentini, “Pulmonary complications: one of the most challenging complications of systemic sclerosis,” Rheumatology, vol. 48, supplement 3, pp. iii40–iii44, 2009. View at Google Scholar · View at Scopus
  76. D. J. Abraham, T. Krieg, J. Distler, and O. Distler, “Overview of pathogenesis of systemic sclerosis,” Rheumatology, vol. 48, supplement 3, pp. iii3–iii7, 2009. View at Publisher · View at Google Scholar
  77. S. Bhattacharyya, J. Wei, and J. Varga, “Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities,” Nature Reviews Rheumatology, vol. 8, no. 1, pp. 42–54, 2012. View at Publisher · View at Google Scholar · View at Scopus
  78. Y. Y. Ho, D. Lagares, A. M. Tager, and M. Kapoor, “Fibrosis—a lethal component of systemic sclerosis,” Nature Reviews Rheumatology, vol. 10, no. 7, pp. 390–402, 2014. View at Publisher · View at Google Scholar · View at Scopus
  79. X. Shi-Wen, M. Eastwood, R. J. Stratton, C. P. Denton, A. Leask, and D. J. Abraham, “Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts,” Rheumatology, vol. 49, no. 2, pp. 259–263, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. A. Antonelli, C. Ferri, S. M. Ferrari et al., “Peroxisome proliferator-activated receptor gamma agonists reduce cell proliferation and viability and increase apoptosis in systemic sclerosis fibroblasts,” British Journal of Dermatology, vol. 168, no. 1, pp. 129–135, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. R. G. Marangoni, B. D. Korman, J. Wei et al., “Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors,” Arthritis & Rheumatology, vol. 67, no. 4, pp. 1062–1073, 2015. View at Google Scholar
  82. Y. Masui, Y. Asano, S. Shibata et al., “Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis,” Journal of the European Academy of Dermatology and Venereology, vol. 26, no. 3, pp. 354–360, 2012. View at Publisher · View at Google Scholar · View at Scopus
  83. H. Arakawa, M. Jinnin, F. C. Muchemwa et al., “Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients,” Experimental Dermatology, vol. 20, no. 9, pp. 764–766, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. C. M. Kusminski and P. E. Scherer, “The road from discovery to clinic: adiponectin as a biomarker of metabolic status,” Clinical Pharmacology & Therapeutics, vol. 86, no. 6, pp. 592–595, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. F. Fang, L. Liu, Y. Yang et al., “The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy,” Arthritis Research and Therapy, vol. 14, article R229, 2012. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Antonelli, S. M. Ferrari, P. Fallahi et al., “Interferon-alpha, -beta and -gamma induce CXCL9 and CXCL10 secretion by human thyrocytes: modulation by peroxisome proliferator-activated receptor-gamma agonists,” Cytokine, vol. 50, no. 3, pp. 260–267, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. B. J. Rabquer, P.-S. Tsou, Y. Hou et al., “Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis,” Arthritis Research & Therapy, vol. 13, no. 1, article R18, 2011. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Antonelli, C. Ferri, P. Fallahi et al., “CXCL10 (α) and CCL2 (β) chemokines in systemic sclerosis—a longitudinal study,” Rheumatology, vol. 47, no. 1, pp. 45–49, 2008. View at Publisher · View at Google Scholar · View at Scopus