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.