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Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis
  1. Christopher P Denton1,
  2. Shiwen Xu1,
  3. Fenge Zhang1,
  4. Rory H Maclean1,
  5. Kristina E N Clark1,
  6. Signe Borchert2,
  7. Rizwan I Hussain2,
  8. Jörg Klingelhöfer2,
  9. Jonas Hallén2,
  10. Voon H Ong1
  1. 1 Centre for Rheumatology, Division of Medicine, UCL, London, UK
  2. 2 Research Department, Arxx Therapeutics, Oslo, Norway
  1. Correspondence to Professor Christopher P Denton, Centre for Rheumatology, UCL, London, NW3 2PF, UK; c.denton{at}


Objectives We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc).

Methods S100A4 protein concentration was measured by ELISA in serum of SSc (n=94) and healthy controls (n=15). Protein expression in skin fibroblast cultures from diffuse cutaneous SSc (SScF, n=6) and healthy controls (normal fibroblasts (NF), n=6) was assessed. Recombinant S100A4 and a high affinity anti-S100A4 neutralising monoclonal antibody (AX-202) were tested on SScF and NF.

Results Median (range) S100A4 (ng/mL) was higher in serum of SSc (89.9 (15.0–240.0)) than healthy controls (71.4 (7.9–131.8); p=0.027). There was association with SSc-interstitial lung disease (p=0.025, n=55), scleroderma renal crisis (p=0.026, n=4). Median (range) S100A4 (ng/mL) was higher in culture supernatants of SScF (4.19 (0.52–8.42)) than NF controls (0.28 (0.02–3.29); p<0.0001). AX-202 reduced the constitutive profibrotic gene and protein expression phenotype of SScF. Genome-wide RNA sequencing analysis identified an S100A4 activated signature in NF overlapping the hallmark gene expression signature of SScF. Thus, 464 differentially expressed genes (false discovery rate (FDR) <0.001 and fold change (FC) >1.5) induced in NF by S100A4 were also constitutively overexpressed, and downregulated by AX-202, in SScF. Pathway mapping of these S100A4 dependent genes in SSc showed the most significant enriched Kegg pathways (FDR <0.001) were regulation of stem cell pluripotency (4.6-fold) and metabolic pathways (1.9-fold).

Conclusion Our findings provide compelling evidence for a profibrotic role for S100A4 in SSc and suggest that serum level may be a biomarker of major organ manifestations and disease severity. This study supports examining the therapeutic potential of targeting S100A4 in SSc.

  • scleroderma, systemic
  • autoantibodies
  • fibroblasts
  • cytokines
  • autoimmune diseases

Data availability statement

Data are available on reasonable request. Study data and protocols will be made available for the purposes of academic research on reasonable request to the corresponding author.

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Data availability statement

Data are available on reasonable request. Study data and protocols will be made available for the purposes of academic research on reasonable request to the corresponding author.

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  • Handling editor Josef S Smolen

  • Contributors CPD, JK and JH conceived the study. CPD, SX, RHM, KENC and VO obtained the data. CPD, VO, JH and XS drafted the manuscript. All authors interpreted the data, edited the manuscript and approved the final submitted version. CPD is responsible for the overall content as guarantor.

  • Funding This study was funded by Norwegian Research Council, research grant to UCL from Arxx Therapeutics, Royal Free Charity (Richard King bequest).

  • Competing interests CPD has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline, consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron, and honoraria from Janssen, Boehringer Ingelheim and Corbus. SB, RIH, JK and JH are employees of Arxx Therapeutics. Other authors have no relevant disclosures.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.