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J Cell Commun Signal. 2012 Jun;6(2):111-3. doi: 10.1007/s12079-012-0160-8. Epub 2012 Feb 15.

Egr-ly awaiting a "personalized medicine" approach to treat scleroderma.

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  • Departments of Dentistry and Physiology and Pharmacology, Dental Sciences Building, University of Western Ontario, London, ON, Canada, N6A 5C1, Andrew.leask@schulich.uwo.ca.


Scleroderma, an autoimmune disorder characterized by skin and organ fibrosis, has no treatment. Although over the past decade valuable insights into the molecular mechanisms underlying scleroderma have been generated, results in clinical trials have been disappointing. This issue is likely to arise due to the heterogeneity of scleroderma. Molecular insights into the heterogeneity of this disease have been provided by genome-wide expression profiling. In a recent paper, Bhattacharyya and colleagues (PLOS One 6:e23082, 2011b) to show that the overexpression of a range of "fibroproliferative" genes in diffuse cutaneous scleroderma patients are likely to be caused by the overexpression of transcription factor Early growth response (Egr)-1. Only a minority of Egr-1-regulated genes were also found to be regulated by TGF-ß. Moreover, Greenblatt and colleagues (Am J Pathol., 2012) have shown that the overexpression of "inflammatory" genes overexpressed in "localized" scleroderma and a small subset of limited and diffuse scleroderma patients is likely to be due to the activity of interleukin-13 (IL-13). Intriguingly, at a gene expression level, murine sclerodermatous graft-versus-host disease (sclGVHD) approximates this inflammatory subset of scleroderma. These data suggest that targeting Egr-1 expression/activity might be a novel therapeutic strategy to control fibrosis in a subset of diffuse scleroderma patients, and further emphasize that notion that elevated canonical TGFβ signaling is insufficient to explain the fibrosis observed in scleroderma. Moreover, targeting IL-13 expression/activity might be a novel therapeutic strategy to target the inflammation leading to "localized" scleroderma.

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