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Abstract Number: 1914

Oncostatin M As a Potential Molecular Target in Systemic Sclerosis

Maria Feeney1, Farhat Syed2, Korsa Khan3, Xu Shiwen4, Katherine Sully5, Sarah Trinder6, Paul Wilson7, David Abraham6,8, Alan M. Holmes6 and Christopher P. Denton9, 1Biopharm Research, GlaxoSmithKline, Stevenage, United Kingdom, 2Immuno-Inflammation, GlaxoSmithKline, Stevenage, United Kingdom, 3Centre For Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom, 4UCL Medical School, London, United Kingdom, 5Biopharm Translational Medicine, GlaxoSmithKline, Stevenage, United Kingdom, 6Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom, 7Quantitative Sciences, GlaxoSmithKline, Stevenage, United Kingdom, 8Centre for Rheumatology and Connective Tissue Disease, University College London, London, United Kingdom, 9Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: cytokines and systemic sclerosis

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Session Information

Date: Monday, November 9, 2015

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  
Oncostatin M (OSM) is a pleiotropic member of the gp130/ IL-6 cytokine family,
produced by a variety of immune cells, including macrophages, neutrophils and
activated T cells.  OSM signals through two receptors; gp130/ LIF low affinity
receptor (LIFR) and gp130/ OSM high affinity receptor (OSMR); activating
JAK/STAT, ERK1/2 and p38 MAPK pathways.  The rationale for the role of OSM in
Systemic Sclerosis (SSc) lies in that key disease components, i.e.
inflammation, vascular dysregulation and fibrosis, complement the biological
activities of the target.

Methods:   Serum OSM levels
were measured by custom OSM ELISA in 63 diffuse cutaneous (Dc) SSc and 18
age-matched healthy donors (HD).  Transcriptomics data derived from published
DcSSc skin biopsies were mined for OSM and known OSM-regulated genes.  The presence of OSM, OSMR, and phospho(p)STAT3 in skin
biopsies from HD (n=12), involved limited cutaneous (Lc)SSc (n=12), and
involved and uninvolved DcSSc (n=13) patients was assessed by
immunohistochemistry (IHC). Primary dermal fibroblasts isolated from HD or
DcSSc skin were incubated with OSM at 2, 20 or 200ng/ml and cell associated
collagen type I (Col-1), and connective tissue growth factor (CTGF) assessed by
Western blot analysis at 24hrs and 72hrs.

Results:   Serum OSM levels
were significantly (P=0.004) increased in DcSSc patients compared with HDs (Table
1).  OSM and OSM-regulated genes, including S100A9 and VCAM-1, were upregulated
in the DcSSc skin.  IHC analysis confirmed OSM, OSMR and pSTAT3 expression in
skin biopsies from SSc patients and HDs, with a similar expression pattern in
both.  SSc skin biopsies exhibited significantly higher inflammatory cell
infiltrates compared to HDs, and were strongly positive for OSM, OSMR and
pSTAT3.  Uninvolved DcSSc skin had significantly more OSM positive immune cell
infiltrates and increased pSTAT3 expression than HDs, but not compared to
involved DcSSc skin.  Involved DcSSc skin exhibited significantly more pSTAT3
positive fibroblasts compared to HDs (p<0.01).  The number of pSTAT3
positive immune cell infiltrates was further significantly enhanced in involved
compared to uninvolved tissue.  Increased numbers of positive OSM and pSTAT3
fibroblasts were present in involved versus uninvolved skin.  OSM induced CTGF
after 24hrs in 4/5 DcSSc dermal fibroblast cell lines tested.  No induction
above baseline was observed in the two HD dermal fibroblast cell lines. 
Following 72hrs stimulation, OSM increased Col-I in 5/7 HD fibroblast lines and
4/7 in the DcSSc fibroblast lines.

Conclusion:   DcSSc
patients have increased OSM serum levels and upregulated OSM and OSM-related
genes in skin biopsies.  In addition, OSM, OSMR and pSTAT3 are increased in
DcSSc skin and dermal fibroblasts from these patients produce Col-I and CTGF in
response to OSM.  These data support targeted approaches to modulating OSM for
the treatment of SSc.


Disclosure: M. Feeney, GSK, 3; F. Syed, GSK, 3; K. Khan, None; X. Shiwen, None; K. Sully, GSK, 3; S. Trinder, None; P. Wilson, GSK, 3; D. Abraham, None; A. M. Holmes, None; C. P. Denton, GlaxoSmithKline, 2,Actelion Pharmaceuticals US, 5,GlaxoSmithKline, 5,Serono, 5,Inventiva, 5,CSL Behring, 2,Bayer, 5.

To cite this abstract in AMA style:

Feeney M, Syed F, Khan K, Shiwen X, Sully K, Trinder S, Wilson P, Abraham D, Holmes AM, Denton CP. Oncostatin M As a Potential Molecular Target in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/oncostatin-m-as-a-potential-molecular-target-in-systemic-sclerosis/. Accessed February 25, 2021.
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