Autoantibodies cause nociceptive sensitization in a mouse model of degenerative osteoarthritis.

Summary

Using the MIA model and human samples, the authors show that B cell–derived IgM autoantibodies drive nociceptive sensitization in osteoarthritic joints, with complement C5a upregulation. Passive transfer of IgM from MIA mice or OA patients induced sensitization, and intra-articular C5aR blockade reduced it.

Key Findings

• B cell–deficient muMT mice failed to develop MIA-induced pain behaviors, indicating B cell dependence of sensitization.
• IgM accumulated in OA joints; intra-articular IgM from MIA mice or OA patients induced nociceptive sensitization in muMT mice, unlike control IgM.
• Complement C5a levels were elevated in MIA joints, and intra-articular C5a receptor blockade (PMX-53) reduced sensitization.

Clinical Implications

Suggests immunomodulatory approaches (e.g., C5a receptor antagonists) and antibody-based biomarkers for OA pain beyond structural joint changes. Highlights potential for stratifying patients by autoantibody profiles.

Limitations

• MIA model may not capture full complexity of human OA pathophysiology
• Limited patient sample characterization; antigen specificity of autoantibodies not defined

Future Directions

Define antigen targets of pronociceptive IgM, validate C5aR antagonism in larger translational studies, and assess prevalence and prognostic value of autoantibody profiles in OA cohorts.