Fibrosis research - from Bedside to Bench and back

Head: Dr. med. Christina Bergmann / Dr. rer. nat. Clara Dees

We study fibrosing diseases using systemic sclerosis (SSc) as a model disease. SSc is characterized by high morbidity and mortality and a variable disease course. We investigate:

  • „Bedside“: Strategies to improve disease progression prediction and risk stratification in SSc.
  • „Bench“: Mechanisms contributing to the maintenance of chronic fibrotic tissue response.

 

„Bedside“-Projects:

  • Investigation of the molecular activity of fibrosing remodeling processes in SSc patients:

Pulmonary fibrosis is a common organ manifestation in SSc and is associated with an increased burden of disease. Although treatment strategies for pulmonary fibrosis have improved in recent years - through improved screening strategies - and expansion of the drug repertoire, management of the disease remains challenging. In particular, this is due to the variable nature of the disease and the difficulty in predicting the individual course of the disease. Fibroblast activation protein (FAP) is a protease that is increased in expression on activated fibroblasts. Recently, 68Ga-labeled FAP inhibitors have become available as PET tracers that selectively label active fibroblasts. In a first proof-of-concept study in cooperation with Prof. Kuwert and PD Dr. Schmidkonz (Nuclear Medicine Clinic), we demonstrated that 68Ga-FAPI-04-uptake is increased in patients with SSc-ILD and that marked 68Ga-FAPI-04 uptake is associated with short-term deterioration (Bergmann C*, Distler JHW*, et al., The Lancet Rheumatology 2021). In this project, we investigate the role of 68Ga-FAPI PET/CT as a potential prognostic factor for SSc-ILD and other fibrosing organ manifestations.

  • European Sclerodermatrials and Research Group (EUSTAR) and Deutsches Netzwerk Systemische Sklerose (DNSS) Register:

We manage the Erlangen cohort of about 370 patients with systemic sclerosis and participate in the databases of the "European Scleroderma trials and Research Group" (EUSTAR) and the "Deutsches Netzwerk Systemische Sklerose" (DNSS). Participation in these projects allows us to collect prospective data to better understand the disease processes in systemic sclerosis and to link them to molecular biology studies. Here, we work on projects both within our center and in cooperation with other SSc centers.

„Bench“-Projects

  • Mechanisms of chronic fibroblast activation.

Fibroblasts are the central effector cells in fibrosing diseases such as SSc. They differentiate into myofibroblasts, which are characterized by a high capacity to produce collagen and other connective tissue proteins. In contrast to the temporary activation of fibroblasts in wound healing processes, which is terminated after the repair process is completed, the fibrotic tissue response in systemic sclerosis initially remains active in an exuberant manner. Several mechanisms may be involved in this (Bergmann C, Distler JHW, et al., Epigenomics 2017; Dees C, et al., Exp Dermatol. 2021): on the one hand, direct, sustained stimulation by profibrotic signaling cascades, and on the other hand, epigenetic changes that occur as a result of stimulation with profibrotic signals. Our group is involved in projects that disentangle the network of profibrotic signaling cascades and mechanisms of epigenetic "reprogramming". Exemplary projects are described below:

  • The role of X-linked inhibitor of apoptosis protein (XIAP) in systemic sclerosis (Bergmann C, et al., ARD 2021).

X-linked inhibitor of apoptosis protein (XIAP) is a member of the IAP family. XIAP is involved in many cellular processes of tissue turnover. In this project, we demonstrated that XIAP is increased in expression in the skin of SSc patients with diffuse, rapidly increasing skin fibrosis and is induced by TGFβ, a key fibrotic mediator. Inhibition of XIAP with pharmacological agents and mRNA-based knockdown results in attenuation of the fibrotic tissue response in several preclinical fibrosis models. These effects are at least partially regulated by the regulation of canonical WNT target genes. Thus, we demonstrated that XIAP represents a key switch point between two profibrotic signaling cascades, the TGFβ and WNT signaling pathways.

  • Epigenetic deregulation of SOCS3 promotes fibroblast activation (Dees C, et al., J Clin Invest 2020).

Methylation of DNA at cytosine is the most studied epigenetic mechanism associated with repression of transcription of the corresponding genes. In fibroblasts from fibrotic tissue of the skin, we demonstrated that Suppressor of Cytokine Signaling 3 (SOCS3), which functions as an endogenous antagonist of the JAK-STAT signaling pathway, is repressed by DNA methylation in the promoter region. Simultaneously, we found increased expression of the DNA methyltransferases DNMT1 and DNMT3A. We demonstrated that TGFβ also plays a central role in these processes. Stimulation with TGFβ induced both activity and expression of DNMT1 and DNMT3A and subsequently methylation of the SOCS3 promoter in quiescent fibroblasts. Failure of SOCS3 subsequently leads to enhancement of the JAK2-STAT3 signaling cascade and increased collagen production. Pharmacological inhibition of DNA methyltransferases resulted in regression of dermal fibrosis.

 

Christina BergmannJunior Research group leader
Clara DeesJunior Research group leader
Sara ChenguitiScientific doctoral student
Saskia BloemenBiological technical assistant
Anna Theresa MüllerMedical doctoral student

 

Deutsche Forschungsgemeinschaft (DFG)
Singe application "The role of X-linked inhibitor of apoptosis protein (XIAP) in Systemic Sclerosis and other fibrosing disorders." (since 2020) - Dr. Christina Bergmann

Single application "Regulation of chromatin remodeling by Notch1 in fibrotic disorders." (since 2021) - Dr. Clara Dees

Single application "The role of SOCS3 in the pathogenesis of fibrotic disorders." (since 2018) - Dr. Clara Dees

Single application "The role of PARP1 in the pathogenesis of fibrotic disorders" (2015-2018) - Dr. Clara Dees

ELAN-Program, Friedrich-Alexander University Erlangen-Nürnberg
"Interactions Hedgehog/AP1" (since 2021) - Dr. Christina Bergmann

J39 - "Hypermethylation of SOCS3 in fibrotic diseases." (2014-2015) - Dr. Clara Dees

"WNT5A" (2017) - Dr. Christina Bergmann

Clinician Scientists Programm, IZKF, Universitätsklinikum Erlangen
Clinician Scientist Rotation position 2021 - Dr. Christina Bergmann

Else Kröner-Fresenius-Stiftung (EKFS)
"Inhibition of Gli2"

Deutsche Stiftung Systemische Sklerose
Research Award 2017 (XIAP project) - Dr. Christina Bergmann

 

  1. Bergmann C*, Distler J*, Treutlein C, Tascilar K, Müller A, Atzinger A, Matei AE, Knitza J, Györfi AH, Lück A, Dees C, Soare A, Ramming A, Schönau V, Distler O, Prante O, Ritt P, Götz TI, Köhner M, Cordes M, Bäuerle T, Kuwert T, Schett G, Schmidkonz C. (2021) 68Ga-FAPI PET/CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study. Lancet Rheumatology. Volume 3, Issue 3;e185-e194. *contributed equally and corresponding author
  2. Bergmann C, Hallenberger L, Chenguiti Fakhouri S, Merlevede B, Brandt A, Dees C, Zhu H, Zehender A, Zhou X, Schwab A, Chen CW, Györfi AH, Matei AE, Chakraborty D, Trinh-Minh T, Rauber S, Coras R, Bozec A, Kreuter A, Ziemer M, Schett G, Distler JHW. (2021) X-linked inhibitor of apoptosis (XIAP) inhibition in systemic sclerosis (SSc). Ann Rheum Dis. 2021 Apr 26:annrheumdis-2020-219822.
  3. Knitza J, Mohn J, Bergmann C, Kampylafka E, Hagen M, Bohr D, Morf H, Araujo E, Englbrecht M, Simon D, Kleyer A, Meinderink T, Vorbrüggen W, von der Decken CB, Kleinert S, Ramming A, Distler JHW, Vuillerme N, Fricker A, Bartz-Bazzanella P, Schett G, Hueber AJ, Welcker M. (2021) Accuracy, patient-perceived usability, and acceptance of two symptom checkers (Ada and Rheport) in rheumatology: interim results from a randomized controlled crossover trial.Arthritis Res Ther. 23(1):112.
  4. Dees C, Chakraborty D, Distler JHW. (2021) Cellular and molecular mechanisms in fibrosis. Exp Dermatol. 30(1):121-131.
  5. Schmidkonz C, Rauber S, Atzinger A, Agarwal R, Götz TI, Soare A, Cordes M, Prante O, Bergmann C, Kleyer A, Ritt P, Maschauer S, Hennig P, Toms J, Köhner M, Manger B, Stone JH, Haberkorn U, Baeuerle T, Distler JHW, Agaimy A, Kuwert T, Schett G, Ramming A. (2020) Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.Ann Rheum Dis. 79(11):1485-1491.
  6. Dees C, Pötter S, Zhang Y, Bergmann C, Zhou X, Luber M, Wohlfahrt T, Karouzakis E, Ramming A, Gelse K, Yoshimura A, Jaenisch R, Distler O, Schett G, Distler JH. (2020) TGFβ induced epigenetic deregulation of SOCS3 facilitates STAT3-signaling to promote fibrosis. J Clin Invest. 130(5):2347-2363.
  7. Zhang Y, Pötter S, Chen CW, Liang R, Gelse K, Ludolph I, Horch RE, Distler O, Schett G, Distler JHW, Dees C. (2018) Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 77(5):744-751.
  8. Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, Pötter S, Zhang Y, Chen CW, Mallano T, Liang R, Kagwiria R, Kreuter A, Pantelaki I, Bozec A, Abraham D, Rieker R, Ramming A, Distler O, Schett G, Distler JHW. (2018) The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 77(1):150-158.
  9. Bergmann C, Distler JH. (2017) Epigenetic factors as drivers of fibrosis in systemic sclerosis. Epigenomics. 9(4):463-477.
  10. Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin NY, Beyer C, Distler O, Schett G, Distler JH. (2014) The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis. 73(6):1232-9.

 

PubMed publication list of Dr. Christina Bergmann

PubMed publication list of Dr. Clara Dees