True origins of arthritis

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.

Researchers have recently discovered that some joints may be more susceptible to inflammatory arthritis before birth, offering new insight into why rheumatoid arthritis attacks particular joints while sparing others.
"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.

The study compared two finger joints that differ in their susceptibility to rheumatoid arthritis. Researchers compared proximal interphalangeal (PIP) joints, which are commonly affected by the disease, and distal interphalangeal (DIP) joints near the fingertips, which are usually spared.

They found that the PIP joints contained larger synovial volumes and higher levels of PI16-positive (PI16+) fibroblasts, a specialized 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.

The embryonic origins of site-specific arthritis. Credit: NDORMS

For decades we have known that rheumatoid arthritis selectively targets particular joints, but one of the great unanswered questions is why?
These new 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.
Researchers 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 specialized 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, both the cartilage and surrounding joint fibroblasts.

The process appeared to be influenced by specific localized 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 joints 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 organization 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 organized 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.
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.

Sarah Davidson et al, The embryonic origins of site-specific arthritis, Nature Immunology (2026). DOI: 10.1038/s41590-026-02542-2