Osteoarthritis: New players involved in joint inflammation
Why do some joints remain chronically inflamed in osteoarthritis and other rheumatic diseases? Researchers have taken an important step toward answering this question. Their findings, published in the international journal Cell Death & Differentiation, highlight the key role of proteins associated with endoplasmic reticulum (ER) stress, a cellular mechanism that has so far been only sparsely investigated in human joint tissues.
The team focused on the synovial membrane, the tissue lining the inside of joints that plays a central role in inflammatory processes. Within our cells, the endoplasmic reticulum acts as a factory responsible for protein production and quality control. When exposed to prolonged stress, particularly in an inflammatory environment, certain proteins known as ER chaperones are produced in larger amounts to help cells maintain their functions despite adverse conditions.
By analyzing tissue samples from patients with osteoarthritis (OA), rheumatoid arthritis (RA), and other inflammatory arthropathies, the researchers mapped, for the first time, the localization of eleven ER stress proteins directly within human joint tissues. They found that the abundance of these proteins increases as inflammation progresses and that they are closely associated with specific populations of fibroblast-like synoviocytes (FLS), cells involved in tissue remodeling and joint damage.
“Our results show that these proteins are not merely markers of cellular stress. They actively contribute to the transformation of cells within the synovial membrane and to the maintenance of inflammation,” explains Zoé Gendebien, researcher at the Rheumatology Laboratory (University of Liège).
A Particularly Promising Protein
Among the proteins investigated, one in particular, PDIA4, drew the researchers' attention. Laboratory experiments demonstrated that reducing the expression of this protein significantly impairs the ability of fibroblast-like synoviocytes to proliferate and migrate, two key mechanisms involved in the development of synovitis, the inflammation of the synovial membrane.
These findings suggest that PDIA4 could represent a promising new therapeutic target for limiting the inflammatory and tissue-destructive processes observed in joint diseases.
“This study sheds light on a biological mechanism that remains poorly understood in joint diseases. By identifying the molecular players involved in the progression of synovitis, we are opening new avenues for the development of more targeted therapies,” says Dominique de Seny, Head of the Rheumatology Laboratory.
Liège Expertise Serving Patients
This work illustrates the expertise developed within the Rheumatology Laboratory of the GIGA Institute and CHU de Liège, at the interface between basic and clinical research. By combining state-of-the-art imaging and cellular analysis technologies with the study of patient samples, the team contributes to a better understanding of the mechanisms underlying rheumatic diseases and helps identify new therapeutic opportunities.
For Professor Clio Ribbens, Head of the Rheumatology Department at Liège University Hospital, this close collaboration is a major strength: “The close relationship between researchers and clinicians allows us to build research projects directly from questions arising in patient care, ensuring that our work remains highly relevant for future clinical management.”
This publication provides new insight into the links between ER stress, inflammation, and tissue remodeling within joints, further highlighting the leading role of Liège-based research in advancing our understanding of rheumatic diseases.
Reference:
Gendebien, Z., Poulet, C., Deroyer, C. et al. Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01841-3
