Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis. - 2026
Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis.
[en] A strong crosstalk exists between endoplasmic reticulum (ER) stress and synovitis. Beyond their canonical role in protein folding, ER stress chaperones may promote inflammation, cell survival, and fibroblast activation under pathological conditions. This study aimed at localizing and quantifying 11 ER stress proteins (BiP, HYOU1, MANF, PDIA4, GANAB, HSP90B1, TXNDC5, DNAJB11, LMAN1, ERP29, CALR) in human inflamed synovial membranes and at investigating their expression in fibroblast-like synoviocytes (FLS) under ER stress, pro-inflammatory, or pro-fibrotic stimuli. By immunohistochemistry, on a first cohort of formalin-fixed paraffin-embedded (FFPE) biopsies obtained from patients with osteoarthritis (OA), chronic pyrophosphate arthropathy (CPPA), and rheumatoid arthritis (RA), these ER chaperones were primarily localized to the lining in low-grade inflammation (Tak <4) and expanded to the sublining under high inflammatory conditions (Tak ≥4), with a widespread distribution in RA. Imaging mass cytometry, applied to a second cohort of FFPE tissue samples collected from patients diagnosed with OA and RA, revealed the co-expression of ER stress proteins with CD55⁺ FLS in the lining and their progressive infiltration into the sublining along with CD34⁺CD31- FLS during inflammation. These observations were confirmed by immunofluorescence on a larger cohort of OA patients. As inflammation progresses, there is a loss of co-expression with CD55 in the lining, accompanied by a gradual shift towards co-expression with CD34 in the sublining. In vitro, ER stress proteins, particularly BiP, HYOU1, MANF, PDIA4, HSP90B1, LMAN1, CALR, and DNAJB11 are overexpressed in human OA FLS following ER stress, pro-inflammatory or pro-fibrotic stimulation, with BiP, PDIA4, HSP90B1, ERP29, and CALR also being secreted. PDIA4 emerged as a central player: its depletion significantly impaired FLS proliferation and migration, highlighting a direct role in driving synovitis. This study provides the first spatial and functional characterization of ER chaperones in human arthritic synovium, linking ER stress to fibroblast plasticity, inflammation, and fibrosis.
Daniel, Christophe ; Université de Liège - ULiège > Département des sciences cliniques
Thirion, Thierry ; Université de Liège - ULiège > Département des sciences cliniques > Anatomie de l'appareil locomoteur et chirurgie de l'appareil locomoteur
Sokolova, Tatiana; Division of Systemic and Inflammatory Rheumatic Diseases, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium
Durez, Patrick; Division of Systemic and Inflammatory Rheumatic Diseases, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium
Hemon, Patrice ; LBAI, UMR1227, Univ Brest, Inserm, Brest, France
Delarue, Yuna; LBAI, UMR1227, Univ Brest, Inserm, Brest, France
Marec, Nadège; LBAI, UMR1227, Univ Brest, Inserm, Brest, France
Bianchi, Elettra ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Ribbens, Clio ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
de Seny, Dominique ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis.
F.R.S.-FNRS - Belgian National Fund for Scientific Research FIRS - CHU Liège. Fonds d'Investissement de Recherche Scientifique Fondation Arthrose Fondation Léon Fredericq
Funding text :
This study was supported by the \u201CFond d\u2019Investissement pour la Recherche Scientifique\u201D (FIRS, Center Hospitalier Universitaire de Li\u00E8ge, Belgium), the Fondation Lejeune-Lechien, the Fondation Arthrose, and a clinical research grant (L\u00E9on Fr\u00E9d\u00E9ricq, Belgium) and the \u201COrganisation Belge CAP48\u201D. ZG is funded by the \u201CFonds National de la Recherche Scientifique\u201D (FNRS).The authors thank the Immunohistochemistry and Imagery platforms of GIGA at the University of Lie\u0300ge for their contribution. The authors acknowledge the cytometry flow core facility Hyperion (Brest, France) for its technical assistance, as well as the European FEDER grant program Progos RU 000950 members of the Scientific Interest Group (GIS) Biogenouest.
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