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

Previous preclinical and translational studies suggest that tissue trauma related to bony fracture and intervertebral disk disruption initiates the formation of pronociceptive antibodies that support chronic musculoskeletal pain conditions. This study tested this hypothesis in the monosodium iodoacetate (MIA) mouse model of osteoarthritis (OA) and extended the findings using OA patient samples. Monosodium iodoacetate was injected unilaterally into the knees of male and female wild-type (WT) and muMT mice (lacking B cells) to induce articular cartilage damage. Repeated nociceptive behavioral testing was performed, and serum was collected for antibody isolation and passive transfer experiments. Serum antibodies collected from patients with OA were tested in MIA-treated muMT mice. Biochemical analyses were performed on knee joint tissues. Monosodium iodoacetate-treated WT mice developed chronic ipsilateral hindlimb allodynia, hyperalgesia, and unweighting, but these pain behaviors were absent in MIA-treated muMT mice, indicating that cartilage injury-induced pain is B-cell dependent. IgM accumulation was observed in the knee tissues of MIA-treated mice, and intra-articular injection of IgM from MIA-treated mice into MIA-treated muMT mice caused nociceptive sensitization. Similarly, intra-articular injection of IgM from patients with OA was pronociceptive in muMT MIA mice and control subject IgM had no effect. Monosodium iodoacetate-injected joints demonstrate elevated levels of complement component 5a (C5a) and C5a receptor blockade using intra-articular PMX-53-reduced sensitization. These data suggest that MIA-treated mice and patients with OA generate pronociceptive antibodies, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain.