Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2020

01-12-2020 | Systemic Sclerosis | Research article

The role of the oncostatin M/OSM receptor β axis in activating dermal microvascular endothelial cells in systemic sclerosis

Authors: G. Marden, Q. Wan, J. Wilks, K. Nevin, M. Feeney, N. Wisniacki, M. Trojanowski, A. Bujor, L. Stawski, M. Trojanowska

Published in: Arthritis Research & Therapy | Issue 1/2020

Login to get access

Abstract

Background

Scleroderma (SSc) is a rare autoimmune disease characterized by vascular impairment and progressive fibrosis of the skin and other organs. Oncostatin M, a member of the IL-6 family, is elevated in SSc serum and was recognized as a significant player in various stages of fibrosis. The goal of this study was to assess the contribution of the OSM/OSMRβ pathway to endothelial cell (EC) injury and activation in SSc.

Methods

IHC and IF were used to assess the distribution of OSM and OSMRβ in SSc (n = 14) and healthy control (n = 7) skin biopsies. Cell culture experiments were performed in human dermal microvascular endothelial cells (HDMECs) and included mRNA and protein analysis, and cell migration and proliferation assays. Ex vivo skin organoid culture was used to evaluate the effect of OSM on perivascular fibrosis.

Results

OSMRβ protein was elevated in dermal ECs and in fibroblasts of SSc patients. Treatments of HDMECs with OSM or IL-6+sIL-6R have demonstrated that both cytokines similarly stimulated proinflammatory genes and genes related to endothelial to mesenchymal transition (EndMT). OSM was more effective than IL-6+sIL-6R in inducing cell migration, while both treatments similarly induced cell proliferation. The effects of OSM were mediated via OSMRβ and STAT3, while the LIFR did not contribute to these responses. Both OSM and IL-6+sIL-6R induced profibrotic gene expression in HDMECs, as well as expansion of the perivascular PDGFRβ+ cells in the ex vivo human skin culture system. Additional studies in HDMECs showed that siRNA-mediated downregulation of FLI1 and its close homolog ERG resulted in increased expression of OSMRβ in HDMECs.

Conclusions

This work provides new insights into the role of the OSM/OSMRβ axis in activation/injury of dermal ECs and supports the involvement of this pathway in SSc vascular disease.
Appendix
Available only for authorised users
Literature
1.
Varga J, Trojanowska M, Kuwana M. Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities. J Scleroderma Relat. 2017;2(3):137–52.CrossRef
2.
John Varga MT, Kuwana M. Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities. J scleroderma relat disord. 2017;2(3):137–52.CrossRef
3.
Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7(10):803–15.PubMedCrossRef
4.
Cho JG, Lee A, Chang W, Lee MS, Kim J. Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction. Front Immunol. 2018;9:294.PubMedPubMedCentralCrossRef
5.
Piera-Velazquez S, Mendoza FA, Jimenez SA. Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases. J Clin Med. 2016;5(4):45.
6.
Manetti M, Romano E, Rosa I, Guiducci S, Bellando-Randone S, De Paulis A, Ibba-Manneschi L, Matucci-Cerinic M. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann Rheum Dis. 2017;76(5):924–34.PubMedCrossRef
7.
Rose-John S. Interleukin-6 Family Cytokines. Cold Spring Harb Perspect Biol. 2018;10(2):a028415.
8.
Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33(11):571–7.PubMedCrossRef
9.
Kishimoto T, Kang S, Tanaka T. IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases. In: Nakao K, Minato N, Uemoto S, eds. Innovative Medicine: Basic Research and Development. Tokyo: Springer; 2015:131–47.
10.
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843–62.PubMedCrossRef
11.
Stawski L, Trojanowska M. Oncostatin M and its role in fibrosis. Connect Tissue Res. 2019;60(1):40–49.
12.
Mozaffarian A, Brewer AW, Trueblood ES, Luzina IG, Todd NW, Atamas SP, Arnett HA. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J Immunol. 2008;181(10):7243–53.PubMedCrossRef
13.
Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-gamma promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) beta2. J Cell Physiol. 2013;228(8):1774–83.PubMedPubMedCentralCrossRef
14.
Richard L, Velasco P, Detmar M. Isolation and culture of microvascular endothelial cells. Methods Mol Med. 1999;18:261–9.PubMed
15.
Karkampouna S, Kloen P, Obdeijn MC, Riester SM, van Wijnen AJ, Kruithof-de Julio M. Human Dupuytren's Ex Vivo Culture for the Study of Myofibroblasts and Extracellular Matrix Interactions. J Vis Exp. 2015;(98):52534.
16.
Stifano G, Sornasse T, Rice LM, Na L, Chen-Harris H, Khanna D, Jahreis A, Zhang Y, Siegel J, Lafyatis R. Skin gene expression is prognostic for the trajectory of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2018;70(6):912–9.PubMedPubMedCentralCrossRef
17.
Ruprecht K, Kuhlmann T, Seif F, Hummel V, Kruse N, Bruck W, Rieckmann P. Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions. J Neuropathol Exp Neurol. 2001;60(11):1087–98.PubMedCrossRef
18.
Yao L, Pan J, Setiadi H, Patel KD, McEver RP. Interleukin 4 or oncostatin M induces a prolonged increase in P-selectin mRNA and protein in human endothelial cells. J Exp Med. 1996;184(1):81–92.PubMedCrossRef
19.
Wijelath ES, Carlsen B, Cole T, Chen J, Kothari S, Hammond WP. Oncostatin M induces basic fibroblast growth factor expression in endothelial cells and promotes endothelial cell proliferation, migration and spindle morphology. J Cell Sci. 1997;110(Pt 7):871–9.PubMedCrossRef
20.
Alexander RA, Prager GW, Mihaly-Bison J, Uhrin P, Sunzenauer S, Binder BR, Schutz GJ, Freissmuth M, Breuss JM. VEGF-induced endothelial cell migration requires urokinase receptor (uPAR)-dependent integrin redistribution. Cardiovasc Res. 2012;94(1):125–35.PubMedCrossRef
21.
Lemos DR, Duffield JS. Tissue-resident mesenchymal stromal cells: Implications for tissue-specific antifibrotic therapies. Sci Transl Med. 2018;10(426):eaan5174.
22.
Ho YY, Baron M, Recklies AD, Roughley PJ, Mort JS. Cells from the skin of patients with systemic sclerosis secrete chitinase 3-like protein 1. BBA Clin. 2014;1:2–11.PubMedPubMedCentralCrossRef
23.
Kumagai E, Mano Y, Yoshio S, Shoji H, Sugiyama M, Korenaga M, Ishida T, Arai T, Itokawa N, Atsukawa M, et al. Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease. Sci Rep. 2016;6:35282.PubMedPubMedCentralCrossRef
24.
Lee CG, Herzog EL, Ahangari F, Zhou Y, Gulati M, Lee CM, Peng X, Feghali-Bostwick C, Jimenez SA, Varga J, et al. Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-beta1 signaling. J Immunol. 2012;189(5):2635–44.PubMedCrossRef
25.
Nordenbaek C, Johansen JS, Halberg P, Wiik A, Garbarsch C, Ullman S, Price PA, Jacobsen S. High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement. Scand J Rheumatol. 2005;34(4):293–7.PubMedCrossRef
26.
Lagendijk AK, Szabo A, Merks RM, Bakkers J. Hyaluronan: a critical regulator of endothelial-to-mesenchymal transition during cardiac valve formation. Trends Cardiovasc Med. 2013;23(5):135–42.PubMedCrossRef
27.
Li Y, Jiang D, Liang J, Meltzer EB, Gray A, Miura R, Wogensen L, Yamaguchi Y, Noble PW. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med. 2011;208(7):1459–71.PubMedPubMedCentralCrossRef
28.
Sanchez-Duffhues G, Garcia de Vinuesa A, Ten Dijke P. Endothelial-to-mesenchymal transition in cardiovascular diseases: developmental signaling pathways gone awry. Dev Dyn. 2018;247(3):492–508.PubMedCrossRef
29.
Daoussis D, Papachristou DJ, Dimitroulas T, Sidiropoulos T, Antonopoulos I, Andonopoulos AP, Liossis SN: Dickkopf-1 is downregulated early and universally in the skin of patients with systemic sclerosis despite normal circulating levels. Clin Exp Rheumatol 2018, 36 Suppl 113(4):45–49.
30.
Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin NY, Beyer C, Distler O, Schett G, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis. 2014;73(6):1232–9.PubMedCrossRef
31.
Chakraborty D, Sumova B, Mallano T, Chen CW, Distler A, Bergmann C, Ludolph I, Horch RE, Gelse K, Ramming A, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun. 2017;8(1):1130.PubMedPubMedCentralCrossRef
32.
Pedroza M, Le TT, Lewis K, Karmouty-Quintana H, To S, George AT, Blackburn MR, Tweardy DJ, Agarwal SK. STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J. 2016;30(1):129–40.PubMedCrossRef
33.
Asano Y, Stawski L, Hant F, Highland K, Silver R, Szalai G, Watson DK, Trojanowska M. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol. 2010;176(4):1983–98.PubMedPubMedCentralCrossRef
34.
Looney AP, Han R, Stawski L, Marden G, Iwamoto M, Trojanowska M. Synergistic role of endothelial ERG and FLI1 in mediating pulmonary vascular homeostasis. Am J Respir Cell Mol Biol. 2017;57(1):121–31.PubMedPubMedCentralCrossRef
35.
Nagai N, Ohguchi H, Nakaki R, Matsumura Y, Kanki Y, Sakai J, Aburatani H, Minami T. Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition. PLoS Genet. 2018;14(11):e1007826.PubMedPubMedCentralCrossRef
36.
Didion SP. Cellular and Oxidative Mechanisms Associated with Interleukin-6 Signaling in the Vasculature. Int J Mol Sci. 2017;18(12):2563.
37.
O'Reilly S, Ciechomska M, Cant R, Hugle T, van Laar JM. Interleukin-6, its role in fibrosing conditions. Cytokine Growth Factor Rev. 2012;23(3):99–107.PubMedCrossRef
38.
Hasegawa M, Sato S, Fujimoto M, Ihn H, Kikuchi K, Takehara K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol. 1998;25(2):308–13.PubMed
39.
Hasegawa M, Sato S, Ihn H, Takehara K. Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Rheumatology (Oxford). 1999;38(7):612–7.CrossRef
40.
Kasembeli MM, Bharadwaj U, Robinson P, Tweardy DJ. Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment. Int J Mol Sci. 2018;19(8):2299.
41.
Dey G, Radhakrishnan A, Syed N, Thomas JK, Nadig A, Srikumar K, Mathur PP, Pandey A, Lin SK, Raju R, et al. Signaling network of Oncostatin M pathway. J Cell Commun Signal. 2013;7(2):103–8.PubMedCrossRef
42.
Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A. 2013;110(42):16975–80.PubMedPubMedCentralCrossRef
43.
Kim KJ, Kwon SH, Yun JH, Jeong HS, Kim HR, Lee EH, Ye SK, Cho CH. STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression. Oncogene. 2017;36(39):5445–59.PubMedCrossRef
44.
Wei Z, Jiang W, Wang H, Li H, Tang B, Liu B, Jiang H, Sun X. The IL-6/STAT3 pathway regulates adhesion molecules and cytoskeleton of endothelial cells in thromboangiitis obliterans. Cell Signal. 2018;44:118–26.PubMedCrossRef
45.
Blanchard F, Wang Y, Kinzie E, Duplomb L, Godard A, Baumann H. Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. J Biol Chem. 2001;276(50):47038–45.PubMedCrossRef
46.
Salvador B, Arranz A, Francisco S, Cordoba L, Punzon C, Llamas MA, Fresno M. Modulation of endothelial function by toll like receptors. Pharmacol Res. 2016;108:46–56.PubMedCrossRef
47.
Murdaca G, Colombo BM, Cagnati P, Gulli R, Spano F, Puppo F. Endothelial dysfunction in rheumatic autoimmune diseases. Atherosclerosis. 2012;224(2):309–17.PubMedCrossRef
48.
Akamata K, Asano Y, Yamashita T, Noda S, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Trojanowska M, Sato S. Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific Fli-1-knockout mice by increasing Fli-1 DNA binding ability. Arthritis Rheumatol. 2015;67(5):1335–44.PubMedPubMedCentralCrossRef
49.
Stawski L, Marden G, Trojanowska M. The activation of human dermal microvascular cells by poly(I:C), lipopolysaccharide, Imiquimod, and ODN2395 is mediated by the Fli1/FOXO3A pathway. J Immunol. 2018;200(1):248–59.PubMedCrossRef
50.
van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, Farina GA, Stifano G, Mathes AL, Cossu M, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014;370(5):433–43.PubMedCrossRef
51.
Yuan L, Nikolova-Krstevski V, Zhan Y, Kondo M, Bhasin M, Varghese L, Yano K, Carman CV, Aird WC, Oettgen P. Antiinflammatory effects of the ETS factor ERG in endothelial cells are mediated through transcriptional repression of the interleukin-8 gene. Circ Res. 2009;104(9):1049–57.PubMedPubMedCentralCrossRef
52.
Saito F, Tasaka S, Inoue K, Miyamoto K, Nakano Y, Ogawa Y, Yamada W, Shiraishi Y, Hasegawa N, Fujishima S, et al. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol. 2008;38(5):566–71.PubMedCrossRef
53.
Kitaba S, Murota H, Terao M, Azukizawa H, Terabe F, Shima Y, Fujimoto M, Tanaka T, Naka T, Kishimoto T, et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol. 2012;180(1):165–76.PubMedCrossRef
54.
Wong S, Botelho FM, Rodrigues RM, Richards CD. Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice. Lab Investig. 2014;94(9):1003–16.PubMedCrossRef
55.
Poling J, Gajawada P, Richter M, Lorchner H, Polyakova V, Kostin S, Shin J, Boettger T, Walther T, Rees W, et al. Therapeutic targeting of the oncostatin M receptor-beta prevents inflammatory heart failure. Basic Res Cardiol. 2014;109(1):396.PubMedCrossRef
56.
Matsuda M, Tsurusaki S, Miyata N, Saijou E, Okochi H, Miyajima A, Tanaka M. Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice. Hepatology. 2018;67(1):296–312.PubMedCrossRef
57.
Botelho FM, Rodrigues R, Guerette J, Wong S, Fritz DK, Richards CD. Extracellular Matrix and Fibrocyte Accumulation in BALB/c Mouse Lung upon Transient Overexpression of Oncostatin M. Cells. 2019;8(2):126.
58.
Iwayama T, Olson LE. Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities. Curr Rheumatol Rep. 2013;15(2):304.PubMedPubMedCentralCrossRef
59.
Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40.PubMedCrossRef
60.
Denton CP, Ong VH, Xu S, Chen-Harris H, Modrusan Z, Lafyatis R, Khanna D, Jahreis A, Siegel J, Sornasse T. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77(9):1362–71.PubMedCrossRef
Metadata
Title
The role of the oncostatin M/OSM receptor β axis in activating dermal microvascular endothelial cells in systemic sclerosis
Authors
G. Marden
Q. Wan
J. Wilks
K. Nevin
M. Feeney
N. Wisniacki
M. Trojanowski
A. Bujor
L. Stawski
M. Trojanowska
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2020
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-020-02266-0

Other articles of this Issue 1/2020

Arthritis Research & Therapy 1/2020 Go to the issue

Research article

Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis

Research article

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

Research article

Favorable efficacy of rituximab in ANCA-associated vasculitis patients with excessive B cell differentiation

Research article

Occurrence of anterior uveitis in patients with spondyloarthritis treated with tumor necrosis factor inhibitors: comparing the soluble receptor to monoclonal antibodies in a large observational cohort

Research article

Detection of subclinical skin manifestation in patients with psoriasis and psoriatic arthritis by fluorescence optical imaging

Research article

The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits