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SAT0020 Molecular characterization of collagen in muscle of polymyositis and dermatomyositis
  1. Z. Liu1,
  2. C. Morehouse1,
  3. B.W. Higgs1,
  4. M. Czapiga1,
  5. M. Rebelatto1,
  6. P. Brohawn1,
  7. L. Richman1,
  8. D. Fiorentino2,
  9. B. Jallal3,
  10. S.A. Greenberg4,
  11. Y. Yao1
  1. 1Translational Sciences, MedImmune, Gaithersburg
  2. 2Stanford University School of Medicine, Stanford
  3. 3Research, MedImmune, Gaithersburg
  4. 4Harvard Medical School, Boston, United States

Abstract

Background Injury of muscle of inflammatory myopathies often results in collagen build-up and a variable degree of fibrosis, which may affect muscle functions. Accompanied with autoimmune responses, elevated type I interferons may be a key components causing muscle damage. Given this persistent inflammatory response in diseased sites of muscle, TGF-β has been identified as the major driver for promoting muscle fibrosis as response for repairing the affected tissues. In addition to promoting collagen synthesis in vitro, it also inhibits collagen degradation. Few efforts have been made to investigate the molecular characteristics of collagens in inflammatory myopathies to date.

Objectives We constructed a molecular signature of collagens in dermatomyositis (DM) and polymyositis (PM), and tried to determine the correlations between collagen expression and disease activity, TGF-β expression-a key regulator of collagen metabolism, and type I interferon activation.

Methods Gene expression profiling was used to identify differentially expressed collagen genes and to develop a collagen gene signature to reflect status of collagen deposition. Relationships between the collagen gene signature and disease activity measured by MMT8 or CLIHAQDI, TGF-β expression, and type I interferon gene signature were examined. Masson’s Trichrome staining for examining collagen deposition in muscles was also conducted to further confirm the association of collagen gene signature and collagen deposition in DM and PM.

Results Elevated transcript expression of collagen subtypes were identified and a collagen gene signature score in muscle was significantly correlated with: 1) disease activity measurements of subjects with PM (MMT8: r = -0.8, p<0.0001, CLIHAQDI: r =0.44, p=0.05); 2) TGF-β transcript level of subjects with PM (r =0.53, p=0.02) or DM (r =0.7, p<0.0001); and 3) a type I interferon gene signature score in subjects with PM (r =0.56, p=0.0098) or DM (DM: r =0.38, p=0.05).

Conclusions A molecular signature for collagens was characterized in DM and PM. Correlation between this signature and disease activity suggests potential utility as a prognostic biomarker. In addition, a significant correlation between this signature and TGF-β expression suggests that inhibiting TGF-β signaling may reduce collagen deposition and fibrosis, providing a potential intervention point for inflammatory myopathies.

Disclosure of Interest Z. Liu Shareholder of: Astra Zeneca, Employee of: MedImmune, C. Morehouse Shareholder of: Astra Zeneca, Employee of: MedImmune, B. Higgs Shareholder of: Astra Zeneca, Employee of: MedImmune, M. Czapiga Shareholder of: Astra Zeneca, Employee of: MedImmune, M. Rebelatto Shareholder of: Astra Zeneca, Employee of: MedImmune, P. Brohawn Shareholder of: Astra Zeneca, Employee of: MedImmune, L. Richman Shareholder of: Astra Zeneca, Employee of: MedImmune, D. Fiorentino: None Declared, B. Jallal Shareholder of: Astra Zeneca, Employee of: MedImmune, S. Greenberg Consultant for: MedImmune, Y. Yao Shareholder of: Astra Zeneca, Employee of: MedImmune

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