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Sarah Davidson
"The embryonic origins of site-specific arthritis" published in Nature Immunology, provides new insight into one of the long-standing mysteries of rheumatoid arthritis: why inflammation targets certain joints while leaving others relatively unaffected.
Rheumatoid arthritis is an autoimmune disease that causes pain, swelling and stiffness when the immune system attacks the synovium, the tissue lining the joints. Over time, this inflammation can damage cartilage, bone and surrounding tissues.
The study compared two finger joints that differ in their susceptibility to rheumatoid arthritis. Researchers compared distal finger joints - known as proximal interphalangeal (PIP) joints, which are commonly affected by the disease, and the distal interphalangeal (DIP) joints near the fingertips, which are usually spared. They found that the PIP joints contained larger synovial volume and higher levels of PI16-positive (PI16+) fibroblasts, a specialised type of connective tissue cell. These differences were established before birth, suggesting that the tissues themselves may play an important role in determining where disease occurs.
Christopher Buckley, Kennedy Professor of Translational Rheumatology at the University of Oxford, said: 'For decades we have known that rheumatoid arthritis selectively targets particular joints, but one of the great unanswered questions is why? Our findings suggest that the answer lies not only in the immune system but also in the tissues themselves. The cellular and structural characteristics established during development may help determine where inflammation takes hold later in life.'
The researchers combined single-cell sequencing, advanced image analysis tools and high-resolution 3D X-ray scanning to create a detailed map of developing human finger joints. Studying joints during development allowed the team to examine entire joints at a level of detail that is difficult to achieve in adult tissue.
They found that the developing joints were made up mainly of structural cells, including cartilage-forming cells and fibroblasts, rather than immune cells. They then investigated what drives these cells to develop into their different specialised forms.
One population that drew particular attention was the synovial lining fibroblasts. These cells produce substances that lubricate the joint to help protect and maintain smooth movement, yet they can also behave abnormally in arthritis. Further analysis suggested that the lining may come from two different sources; from both the cartilage and surrounding joint fibroblasts. The process appeared to be influenced by specific localised signals such as low oxygen levels. This may provide insights into the mechanisms driving their function and help identify ways to restore their normal protective role in disease.
The researchers found important differences between the PIP and DIP joints. A bespoke image analysis tool showed that Pi16+ fibroblasts, that were enriched in the PIP, were specifically located around blood vessels and at sites where tendons and ligaments connect with surrounding tissue. They also showed that PI16+ fibroblasts responded differently to inflammatory signals compared with other fibroblast populations. While PI16+ fibroblasts shared a common pro-inflammatory response with PI16- fibroblasts, they also displayed distinct changes in pathways linked to tissue organisation and immune regulation.
The team also identified striking structural differences between the joints. Using high-resolution 3D imaging at Diamond Light Source at the Harwell Science and Innovation Campus, they found that the synovial tissue surrounding PIP joints was larger and organised differently from that seen in joints that are not usually affected by rheumatoid arthritis. Together, these cellular and structural differences may help explain why inflammation develops in some locations but not others.
Dr Sarah Davidson, Postdoctoral Researcher at the Kennedy Institute and one of the first authors of the study, said: 'We found that joints commonly affected by rheumatoid arthritis already contain distinct cellular populations before birth. PI16+ fibroblasts were enriched in vulnerable joints and responded differently to inflammatory signals. Their location and behaviour suggest they could help shape where disease develops.'
Together, the findings suggest that the tendency of rheumatoid arthritis to affect particular joints may be shaped by tissue architecture established during development. Rather than being determined by immune activity alone, vulnerability to inflammation may depend on the local cellular and structural environment of each joint.
The study was led by researchers at the Kennedy Institute of Rheumatology, University of Oxford, in collaboration with the University of Birmingham, University College London and Diamond Light Source.
It was supported by the Medical Research Council (MRC).