Matrix-mediated activation of murine fibroblast-like synoviocytes

Isabel Zeinert; Luisa Schmidt; Till Baar; Giulio Gatto; Anna De Giuseppe; Adelheid Korb-Pap; Thomas Pap; Esther Mahabir; Frank Zaucke; Bent Brachvogel; Marcus Krüger; Thomas Krieg; Beate Eckes

doi:10.1016/j.yexcr.2025.114408

Matrix-mediated activation of murine fibroblast-like synoviocytes

Exp Cell Res. 2025 Jan 5;445(1):114408. doi: 10.1016/j.yexcr.2025.114408. Online ahead of print.

Authors

Isabel Zeinert¹, Luisa Schmidt², Till Baar³, Giulio Gatto⁴, Anna De Giuseppe⁵, Adelheid Korb-Pap⁵, Thomas Pap⁵, Esther Mahabir⁶, Frank Zaucke⁴, Bent Brachvogel⁷, Marcus Krüger⁸, Thomas Krieg⁹, Beate Eckes¹⁰

Affiliations

¹ Translational Matrix Biology, University of Cologne, Medical Faculty, Cologne, Germany. Electronic address: [email protected].
² Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
³ Institute for Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany.
⁴ Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Trauma Surgery and Orthopedics, Goethe University Frankfurt, University Hospital, Frankfurt am Main, Germany.
⁵ Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany.
⁶ Comparative Medicine, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁷ Center for Biochemistry, University of Cologne, Faculty of Medicine, Cologne, Germany; Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸ Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
⁹ Translational Matrix Biology, University of Cologne, Medical Faculty, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹⁰ Translational Matrix Biology, University of Cologne, Medical Faculty, Cologne, Germany. Electronic address: [email protected].

PMID: 39765309
DOI: 10.1016/j.yexcr.2025.114408

Abstract

Fibroblast-like synoviocytes (FLS) are key cells promoting cartilage damage and bone loss in rheumatoid arthritis (RA). They are activated to assume an invasive and migratory phenotype. While mechanisms of FLS activation are unknown, evidence suggests that pre-damaged extracellular matrix (ECM) of the cartilage can trigger FLS activation. Integrin α11β1 might be involved in the activation, as it is increased in RA patients and hTNFtg mice, an RA mouse model. We treated murine chondrocytes with TNFα to produce a damaged, RA-like matrix. Comparison to healthy chondrocyte matrix revealed decreased ECM proteins, e.g. collagens and proteoglycans, increased matrix-degrading proteins and elevated levels of inflammatory cytokines. FLS responded to the damaged chondrocyte matrix with a matrix-remodeling and pro-inflammatory phenotype characterized by a gene signature involved in matrix degradation and increased production of CLL11 and CCL19. Damaged chondrocyte matrix stimulated increased Itga11 expression in FLS, correlating with the increased α11β1 amounts in RA patients. FLS deficient in integrin α11β1 released lower amounts of inflammation-associated cytokines. Our results demonstrate differences in healthy and RA-like chondrocyte ECM and distinctly different responses of wt FLS to damaged versus healthy ECM.

Keywords: Chondrocytes; Cytokines; Extracellular matrix; Rheumatoid arthritis.