Platelets play role in rheumatoid arthritis

Platelets from blood smear

Researchers primarily from Harvard Medical School were curious about whether platelets participated in a common inflammatory condition other than atherosclerosis.

So Eric Boilard, PhD, from Harvard Medical School in Boston, Massachusetts, and colleagues used the platelet-specific marker CD41 and flow cytometry to determine that a substantial number of CD41-positivie events occurred in rheumatoid arthritis (RA) synovial fluids (SA). They concluded that these particles were platelet microparticles (MPs) because they were smaller in size than intact leukocytes or platelets.

They also observed that SF from patients with RA had an average of 2 x 10⁵ CD41-positive MPs per microliter, while patients with osteoarthritis had undetectable levels of CD41-positive MPs.

The researchers then investigated the importance of platelet MPs in RA in vivo by using the K/BxN serum transfer mouse model. They treated these mice with an antibody that depleted more than 95% of their platelets within 60 minutes. The platelet-depleted mice had markedly reduced arthritis, demonstrating that platelets are required to develop inflammatory arthritis.

The investigators then considered how platelets are linked to joint inflammation by studying the thromboxane A2 pathway, the P2Y12 pathway, and the GPIb-IX pathway. Blockade of these pathways in mice did not curtail joint inflammation. This suggested that these pathways do not regulate the generation of platelet MPs in inflammatory arthritis.

The team then hypothesized that platelet activation occurs locally, in the fibroblast-like synoviocytes (FLS) and their extracellular matrix. They used platelets isolated from mice deficient in candidate genes and found that the cyclooxygenase, thromboxane, and ADP-P2Y12 pathways were not necessary for inflammation, which was consistent with the in vivo data.

Using platelets lacking either FcR-γ-chain or glycoprotein VI (GPVI), the team established that the collagen receptor GPVI mediated the generation of MPs by primary FLS in both mice and humans.

They also observed the inflammatory cytokine IL-6 and the neutrophil chemoattractant IL-8 in collagen-stimulated human platelet MPs. Upon further study, they found that FLS from mice deficient in the IL-1 receptor did not respond to platelet MPs. The investigators stated, however, that “IL-1 is unlikely to be the only relevant platelet mediator in the synovial environment.”

The investigators believe that the “relevance of these results for human disease is substantial,” and that GPVI receptor antagonism represents a novel therapeutic approach to treating inflammatory arthritis.

These findings were reported January 29 in the journal Science.