Fibrin deposition associates with cartilage degeneration in arthritis

EBioMedicine. 2022 Jul;81:104081. doi: 10.1016/j.ebiom.2022.104081. Epub 2022 May 31.

Abstract

Background: Cartilage damage in inflammatory arthritis is attributed to inflammatory cytokines and pannus infiltration. Activation of the coagulation system is a well known feature of arthritis, especially in rheumatoid arthritis (RA). Here we describe mechanisms by which fibrin directly mediates cartilage degeneration.

Methods: Fibrin deposits were stained on cartilage and synovial tissue of RA and osteoarthritis (OA) patients and in murine adjuvant-induced arthritis (AIA) in wild-type or fibrinogen deficient mice. Fibrinogen expression and procoagulant activity in chondrocytes were evaluated using qRT-PCR analysis and turbidimetry. Chondro-synovial adhesion was studied in co-cultures of human RA cartilage and synoviocytes, and in the AIA model. Calcific deposits were stained in human RA and OA cartilage and in vitro in fibrinogen-stimulated chondrocytes.

Findings: Fibrin deposits on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA in wild-type mice, whilst fibrinogen deficient mice were protected. Fibrin upregulated Adamts5 and Mmp13 in chondrocytes. Chondro-synovial adhesion only occurred in fibrin-rich cartilage areas and correlated with cartilage damage. In vitro, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-rich areas. Fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization by inducing pro-calcification genes (Anx5, Pit1, Pc1) and the IL-6 cytokine. Similar fibrin-mediated mechanisms were observed in OA models, but to a lesser extent and without pseudo-membranes formation.

Interpretation: In arthritis, fibrin plaques directly impair cartilage integrity via a triad of catabolism, adhesion, and calcification.

Funding: None.

Keywords: Arthritis; Calcification; Cartilage degradation; Chondro-synovial adhesion; Fibrin; Fibrinogen.

MeSH terms

  • Animals
  • Arthritis, Rheumatoid* / metabolism
  • Cartilage / metabolism
  • Chondrocytes / metabolism
  • Fibrin / metabolism
  • Fibrinogen / genetics
  • Fibrinogen / metabolism
  • Humans
  • Mice
  • Osteoarthritis* / genetics
  • Osteoarthritis* / metabolism
  • Synovial Membrane

Substances

  • Fibrin
  • Fibrinogen