Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Annals of the rheumatic diseases - 82(2023), 9 vom: 06. Sept., Seite 1205-1217 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Denton, Christopher P [VerfasserIn] |
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| Links: |
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| Themen: |
Autoantibodies |
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| Anmerkungen: |
Date Completed 14.08.2023 Date Revised 14.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/ard-2023-223862 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359156304 |
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| 100 | 1 | |a Denton, Christopher P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 14.08.2023 | ||
| 500 | |a Date Revised 14.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a OBJECTIVES: We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc) | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a autoantibodies | |
| 650 | 4 | |a autoimmune diseases | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a fibroblasts | |
| 650 | 4 | |a scleroderma, systemic | |
| 700 | 1 | |a Xu, Shiwen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Fenge |e verfasserin |4 aut | |
| 700 | 1 | |a Maclean, Rory H |e verfasserin |4 aut | |
| 700 | 1 | |a Clark, Kristina E N |e verfasserin |4 aut | |
| 700 | 1 | |a Borchert, Signe |e verfasserin |4 aut | |
| 700 | 1 | |a Hussain, Rizwan I |e verfasserin |4 aut | |
| 700 | 1 | |a Klingelhöfer, Jörg |e verfasserin |4 aut | |
| 700 | 1 | |a Hallén, Jonas |e verfasserin |4 aut | |
| 700 | 1 | |a Ong, Voon H |e verfasserin |4 aut | |
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