• Something wrong with this record ?

S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin

X. Švec, H. Štorkánová, T. Trinh-Minh, MC. Tran, L. Štorkánová, H. Hulejová, S. Oreská, B. Heřmánková, R. Bečvář, K. Pavelka, J. Vencovský, J. Klingelhöfer, RI. Hussain, J. Hallén, L. Šenolt, JHW. Distler, M. Tomčík

. 2024 ; 63 (3) : 817-825. [pub] 20240301

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24007017

Grant support
023728 Ministry of Health of the Czech Republic
Ministry of Education Youth and Sports
SVV 260638 Czech Republic
German Research Foundation
2013.056.1 German Research Foundation

OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24007017
003      
CZ-PrNML
005      
20240423155648.0
007      
ta
008      
240412s2024 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1093/rheumatology/kead295 $2 doi
035    __
$a (PubMed)37314987
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Švec, Xiao $u Institute of Rheumatology, Prague, Czech Republic $u 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000157009055
245    10
$a S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin / $c X. Švec, H. Štorkánová, T. Trinh-Minh, MC. Tran, L. Štorkánová, H. Hulejová, S. Oreská, B. Heřmánková, R. Bečvář, K. Pavelka, J. Vencovský, J. Klingelhöfer, RI. Hussain, J. Hallén, L. Šenolt, JHW. Distler, M. Tomčík
520    9_
$a OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
650    _2
$a zvířata $7 D000818
650    _2
$a lidé $7 D006801
650    _2
$a myši $7 D051379
650    12
$a alarminy $7 D000067531
650    _2
$a monoklonální protilátky $x farmakologie $7 D000911
650    _2
$a bleomycin $x toxicita $7 D001761
650    _2
$a modely nemocí na zvířatech $7 D004195
650    _2
$a S100 kalcium vázající protein A4 $x genetika $7 D000071999
650    12
$a kůže $x patologie $7 D012867
650    _2
$a fibróza $7 D005355
655    _2
$a časopisecké články $7 D016428
700    1_
$a Štorkánová, Hana $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000264168385 $7 xx0213301
700    1_
$a Trinh-Minh, Thuong $u Clinic for Rheumatology, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany $u Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany
700    1_
$a Tran, Manh Cuong $u Clinic for Rheumatology, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany $u Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany
700    1_
$a Štorkánová, Lenka $u Institute of Rheumatology, Prague, Czech Republic
700    1_
$a Hulejová, Hana $u Institute of Rheumatology, Prague, Czech Republic $1 https://orcid.org/0000000223356996 $7 xx0077461
700    1_
$a Oreská, Sabína $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/000000029912725X
700    1_
$a Heřmánková, Barbora $u Institute of Rheumatology, Prague, Czech Republic $u Department of Physiotherapy, Faculty of Physical Education and Sport, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000213141123
700    1_
$a Bečvář, Radim $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000300223135 $7 jx20050531010
700    1_
$a Pavelka, Karel $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000319528422 $7 jn99240000847
700    1_
$a Vencovský, Jiří $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000208510713 $7 jo20000080529
700    1_
$a Klingelhöfer, Jörg $u Arxx Therapeutics, Oslo, Norway $1 https://orcid.org/0000000159284755
700    1_
$a Hussain, Rizwan I $u Arxx Therapeutics, Oslo, Norway $u Agiana Pharmaceuticals, Oslo, Norway $1 https://orcid.org/0000000300519075
700    1_
$a Hallén, Jonas $u Arxx Therapeutics, Oslo, Norway
700    1_
$a Šenolt, Ladislav $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000155007312 $7 xx0056558
700    1_
$a Distler, Jörg H W $u Clinic for Rheumatology, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany $u Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine University, Düsseldorf, Germany $1 https://orcid.org/0000000174089333
700    1_
$a Tomčík, Michal $u Institute of Rheumatology, Prague, Czech Republic $u Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic $1 https://orcid.org/0000000286167850 $7 xx0200375
773    0_
$w MED00011379 $t Rheumatology $x 1462-0332 $g Roč. 63, č. 3 (2024), s. 817-825
856    41
$u https://pubmed.ncbi.nlm.nih.gov/37314987 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20240412 $b ABA008
991    __
$a 20240423155645 $b ABA008
999    __
$a ok $b bmc $g 2081179 $s 1216784
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 63 $c 3 $d 817-825 $e 20240301 $i 1462-0332 $m Rheumatology $n Rheumatology (Oxford) $x MED00011379
GRA    __
$a 023728 $p Ministry of Health of the Czech Republic
GRA    __
$p Ministry of Education Youth and Sports
GRA    __
$a SVV 260638 $p Czech Republic
GRA    __
$p German Research Foundation
GRA    __
$a 2013.056.1 $p German Research Foundation
LZP    __
$a Pubmed-20240412

Find record

Citation metrics

Archiving options